Bimodal release ondansetron tablets and methods of treating nausea and vomiting

ABSTRACT

A solid oral dosage form includes a core comprising a non-ionic polymer matrix, a first amount of a first antiemetic drug or a pharmaceutically acceptable salt thereof dispersed within the matrix, and a salt dispersed within the matrix; a first seal coat of a non-ionic polymer matrix surrounding the core; and an immediate release drug layer surrounding the first seal coat, wherein the immediate release drug layer comprises a non-ionic polymer and a second amount of a second antiemetic drug or a pharmaceutically acceptable salt thereof dispersed therein, wherein the drug layer is sufficiently designed to release the second amount of the antiemetic drug over a period of at least 1 hour, wherein the solid oral dosage form is sufficiently designed to release the first amount of the first antiemetic drug and the second amount of the second antiemetic drug over a minimum period of 16 hours.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/466,214, filed Mar. 22, 2017, which is a continuation of U.S.application Ser. No. 14/212,694, filed Mar. 14, 2014, now U.S. Pat. No.9,636,305, which claims the benefit of and priority to U.S. provisionalApplication Ser. No. 61/782,395, filed Mar. 14, 2013, the entiredisclosure of each of which is incorporated herein by reference in theirentirety.

BACKGROUND

The 5-HT₃ antagonists are a class of drugs that act as receptorantagonists at the 5-HT₃ receptor, a subtype of serotonin receptor foundin terminals of the vagus nerve and in certain areas of the brain. Withthe notable exception of alosetron and cilansetron, which are used inthe treatment of irritable bowel syndrome, all 5-HT₃ antagonists areantiemetics, used in the prevention and treatment of nausea andvomiting. They are particularly effective in controlling the nausea andvomiting produced by cancer chemotherapy and are considered the goldstandard for this purpose. Ondansetron is a serotonin 5-HT₃ receptorantagonist used alone or with other medications to prevent nausea andvomiting, and is used for preventing nausea and vomiting caused bycancer drug treatment (chemotherapy) and radiation therapy. It is alsoused to prevent and treat nausea and vomiting after surgery.

SUMMARY

Extended release solid dosage forms are disclosed herein. Moreparticularly, antiemetic extended release solid dosage forms aredisclosed herein for preventing nausea and vomiting. According toaspects illustrated herein, there is disclosed an extended releaseondansetron tablet that includes a core comprising a sustained releaseagent comprising ondansetron, or a pharmaceutically acceptable saltthereof, and an electrolyte; a first seal coating agent; an immediaterelease drug layer surrounding the first seal coating agent comprisingondansetron, or a pharmaceutically acceptable salt thereof; and a secondseal coating agent, wherein the immediate release layer is sufficientlydesigned to release about ¼ of a total dose of ondansetron within about1 hour after oral administration, and wherein the core is sufficientlydesigned to release the remaining dose of ondansetron for a period of upto 24-hours via zero-order release. In an embodiment, the core comprisesabout 18 mg of ondansetron free base. In an embodiment, the corecomprises about 20 mg of ondansetron free base. In an embodiment, thecore comprises about 28 mg of ondansetron free base. In an embodiment,the electrolyte is sodium dihydrogen citrate anhydrous present at aconcentration in the range of about 50% to about 100% by weight of thesustained release agent. In an embodiment, the sustained release agentis a hydrophilic swellable matrix. In an embodiment, the hydrophilicswellable matrix of the core is METHOCEL™ K4M Premium DC, thehypromellose of the first seal coating and the second seal coating isMETHOCEL™ E5 Premium LV, and the hypromellose of the immediate releasedrug layer is METHOCEL™ E5 Premium LV. In an embodiment, the hydrophilicswellable matrix of the core is METHOCEL™ K4M Premium CR, thehypromellose of the first seal coating and the second seal coating isMETHOCEL™ E5 Premium LV, and the hypromellose of the immediate releasedrug layer is METHOCEL™ E5 Premium LV. In an embodiment, the immediaterelease layer comprises about 6 mg of ondansetron.

According to aspects illustrated herein, there is disclosed an extendedrelease ondansetron tablet that includes a core comprising a hydrophilicswellable matrix comprising ondansetron, or a pharmaceuticallyacceptable salt thereof, and sodium dihydrogen citrate anhydrous; afirst seal coating comprising hypromellose and plasACRYL™; an immediaterelease drug layer surrounding the first seal coating comprisingondansetron, or a pharmaceutically acceptable salt thereof, hypromelloseand plasACRYL™; and a second seal coating comprising hypromellose andplasACRYL™ T20, wherein the immediate release layer is sufficientlydesigned to release about ¼ of a total dose of ondansetron within about1 hour after oral administration, and wherein the core is sufficientlydesigned to release the remaining dose of ondansetron for a period of upto 24-hours via zero-order release. In an embodiment, the core comprisesabout 18 mg of ondansetron free base. In an embodiment, the corecomprises about 20 mg of ondansetron free base. In an embodiment, thecore comprises about 28 mg of ondansetron free base. In an embodiment,the sodium citrate anhydrous is present at a concentration in the rangeof about 50% to about 100% by weight of the hydrophilic swellablematrix. In an embodiment, the hydrophilic swellable matrix of the coreis METHOCEL™ K4M Premium DC, the hypromellose of the first seal coatingand the second seal coating is METHOCEL™ E5 Premium LV, and thehypromellose of the immediate release drug layer is METHOCEL™ E5 PremiumLV. In an embodiment, the hydrophilic swellable matrix of the core isMETHOCEL™ K4M Premium CR, the hypromellose of the first seal coating andthe second seal coating is METHOCEL™ E5 Premium LV, and the hypromelloseof the immediate release drug layer is METHOCEL™ E5 Premium LV. In anembodiment, the immediate release layer comprises about 6 mg ofondansetron.

According to aspects illustrated herein, there is disclosed an extendedrelease solid dosage form that includes an internal portion, wherein theinternal portion comprises a first dose of at least one serotoninantagonist; a first coating, wherein the first coating directlyencapsulates the internal portion of the solid dosage form; a drug layercoating, wherein the drug layer coating directly encapsulates the firstcoating, wherein the drug layer coating comprises a second dose of theat least one serotonin antagonist, wherein the drug layer coating is atleast 4%, by weight, of the solid dosage form, wherein the second doseis equal to at least 15%, by weight, of a total dose of the at least oneserotonin antagonist in the solid dosage form, and wherein the firstdose is equal to the total dose minus the second dose; and a secondcoating, wherein the second coating directly encapsulates the drug layercoating, wherein the internal portion has solubility in water of X,wherein the first coating, the drug layer coating, and the secondcoating have solubility in water of at least Y, and wherein X is lessthan Y. In an embodiment, the at least one serotonin-3 receptorantagonist is ondansetron hydrochloride. In an embodiment, the seconddose is equal to at least 20%, by weight, of the total dose of the atleast one serotonin-3 receptor antagonist in the solid dosage form. Inan embodiment, the at least one serotonin-3 receptor antagonist isondansetron hydrochloride. In an embodiment, the second dose is equal toat least 25%, by weight, of the total dose of the at least oneserotonin-3 receptor antagonist in the solid dosage form. In anembodiment, the first coating and the second coating comprise ahydrophilic material. In an embodiment, the drug layer further comprisesa hydrophilic material. In an embodiment, the hydrophilic material ishypromellose. In an embodiment, the first coating and the second coatingare each of at least 1.5%, by weight, of the solid dosage form. In anembodiment, the ratio of the hypromellose to the at least oneserotonin-3 receptor antagonist in the drug layer is about 4:6. In anembodiment, a total amount of hypromellose in the first coating, thedrug layer, and the second coating is less than 4%, by weight, of thesolid dosage form. In an embodiment, the core further comprises sodiumcitrate in an amount of less than 15%, by weight, of the core. In anembodiment, X is sufficiently less than Y so that the second dose issubstantially released from the solid dosage form within less than 12hours after the solid dosage form is exposed to an aqueous environment,and the first dose is substantially released from the solid dosage in azero-order release profile over a period of 12 to 24 hours after thesolid dosage form is exposed to the aqueous environment. In anembodiment, the aqueous environment has a pH in the range of pH 1.5 topH 7.5. In an embodiment, the solid dosage form is compressed into atablet. In an embodiment, the solid dosage form is formed as a capsule.In an embodiment, the core further comprises glycine in an amount ofless than 20%, by weight, of the core.

According to aspects illustrated herein, there is disclosed an extendedrelease ondansetron tablet made by compressing a sustained release coretablet and then coating the core tablet with a first seal coat followedby drug coat and finally a second seal coat, wherein the core tabletcomprises a hydrophilic swellable matrix comprising ondansetronhydrochloride and sodium dihydrogen citrate anhydrous, wherein the firstseal coat comprises comprising hypromellose and plasACRYL™, wherein thedrug coat comprises ondansetron hydrochloride, hypromellose andplasACRYL™, and wherein the second seal coat comprises hypromellose andplasACRYL™ T20.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising a non-ionic polymer matrix,a first amount of a first antiemetic drug or a pharmaceuticallyacceptable salt thereof dispersed within the matrix, and a saltdispersed within the matrix; a first seal coat surrounding the core,wherein the first seal coat is comprised of a non-ionic polymer matrix;and an immediate release drug layer surrounding the first seal coat,wherein the immediate release drug layer comprises a non-ionic polymerand a second amount of a second antiemetic drug or a pharmaceuticallyacceptable salt thereof dispersed therein, wherein the drug layer issufficiently designed to release the second amount of the antiemeticdrug over a period of at least 1 hour, wherein the solid oral dosageform is sufficiently designed to release the first amount of the firstantiemetic drug and the second amount of the second antiemetic drug overa minimum period of 16 hours.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising hypromellose, 18 mg ofondansetron or an equivalent amount of an ondansetron salt thereof, andsodium citrate anhydrous; a first seal coat surrounding the core andcomprising hypromellose; and an immediate release drug layer surroundingthe first seal coat and comprising hypromellose and 6 mg of ondansetronor an equivalent amount of an ondansetron salt thereof, the immediaterelease drug layer sufficient to release the ondansetron over a periodof at least 1 hour, wherein the total amount of ondansetron in thedosage form is released over 24 hours.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising a non-ionic polymer matrix,a first amount of ondansetron or an equivalent amount of an ondansetronsalt thereof dispersed within the matrix, and a salt dispersed withinthe matrix; a first seal coat surrounding the core, wherein the firstseal coat is comprised of a non-ionic polymer matrix; and an immediaterelease drug layer surrounding the first seal coat, wherein theimmediate release drug layer comprises a non-ionic polymer and a secondamount of ondansetron or an equivalent amount of an ondansetron saltthereof dispersed therein, wherein the solid oral dosage form results inan in vitro ondansetron dissolution profile when measured in a type 2paddle dissolution apparatus at 37° C. in aqueous solution containingdistilled water at 50 rpm that exhibits: a) from about 20% to 50% of thetotal ondansetron is released after two and a half hours of measurementin the apparatus; b) from about 50% to 70% of the total ondansetron isreleased after five hours of measurement in the apparatus; and c) noless than about 90% of the total ondansetron is released after fifteenhours of measurement in the apparatus.

According to aspects illustrated herein, there is disclosed a packagedpharmaceutical preparation that includes a plurality of the solid oraldosage forms of the present invention in a sealed container andinstructions for administering the dosage forms orally to effectprevention of nausea and vomiting

According to aspects illustrated herein, there is disclosed apharmaceutical preparation that includes a plurality of the solid oraldosage forms of the present invention each in a discrete sealed housing,and instructions for administering the dosage forms orally to effectprevention of nausea and vomiting.

According to aspects illustrated herein, there is disclosed a method forcontrolling nausea and vomiting comprising administering a solid dosageform of the present invention to a patient, wherein nausea and vomitingare controlled after an amount of ondansetron has been released from thesolid dosage form, reaches the systemic circulation of the patient, andis absorbed by the patient.

According to aspects illustrated herein, there is disclosed a method forreducing side effects of chemotherapy treatment comprising administeringa solid dosage form of the present invention to a patient, wherein sideeffects including nausea and vomiting are reduced after an amount ofondansetron has been released from the solid dosage form, is absorbed bythe patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed a method forreducing side effects of motion sickness comprising administering asolid dosage form of the present invention to a patient, wherein sideeffects including nausea and vomiting are reduced after an amount ofondansetron has been released from the solid dosage form, is absorbed bythe patient, and reaches the systemic circulation of the patient.

According to aspects illustrated herein, there is disclosed a method forreducing side effects of anesthetics comprising administering a soliddosage form of the present invention to a patient after the patient hasbeen exposed to an anesthetic, wherein side effects including nausea andvomiting are reduced after an amount of ondansetron has been releasedfrom the solid dosage form, is absorbed by the patient, and reaches thesystemic circulation of the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The presently disclosed embodiments will be further explained withreference to the attached drawings. The drawings shown are notnecessarily to scale, with emphasis instead generally being placed uponillustrating the principles of the presently disclosed embodiments.

FIG. 1 illustrates the dissolution profiles of ondansetron from twoembodiments of extended release solid dosage forms of the presentdisclosure as measured using a USP type 2 (paddle) dissolution system at50 rpm, at a temperature of 37±0.5° with distilled water as adissolution medium.

FIG. 2 illustrates the dissolution profile of ondansetron from anembodiment of an extended release solid dosage form of the presentdisclosure as measured using a USP type 2 (paddle) dissolution system at50 rpm, at a temperature of 37±0.5° with 0.1N HCL and pH 6.8 phosphatebuffer as a dissolution medium.

FIG. 3 illustrates the dissolution profile of ondansetron from anembodiment of an extended release solid dosage form of the presentdisclosure as measured using a USP type 2 (paddle) dissolution system at50 rpm, at a temperature of 37±0.5° with 0.1N HCL and pH 6.8 phosphatebuffer as a dissolution medium.

FIG. 4 illustrates the dissolution profiles of ondansetron from anembodiment of an extended release solid dosage form of the presentdisclosure as measured using a USP type 2 (paddle) dissolution system at50 rpm, at a temperature of 37±0.5° with physiologically relevant mediawithin a pH range of 1.2 to 7.2, approximating levels found through theGI tract.

FIG. 5 illustrates the mean measured plasma concentration versus timeprofile of ondansetron, derived from the administration of variousembodiments of extended release solid dosage forms of the presentdisclosure and a reference product.

FIG. 6 illustrates the ln-transformed mean concentration versus timeprofile of ondansetron, derived from the administration of variousembodiments of extended release solid dosage forms of the presentdisclosure and a reference product.

FIG. 7 illustrates the linear mean measured plasma concentration versustime profile of Test Product at day 1, derived from the administrationof an embodiment of an extended release solid dosage form of the presentdisclosure and a reference product.

FIG. 8 illustrates the linear mean measured plasma concentration versustime profile of Test Product at day 2, derived from the administrationof an embodiment of an extended release solid dosage form of the presentdisclosure and a reference product.

FIG. 9 illustrates the ln-transformed mean concentration versus timeprofile of Test Product at day 1, derived from the administration of anembodiment of an extended release solid dosage form of the presentdisclosure and a reference product.

FIG. 10 illustrates the ln-transformed mean concentration versus timeprofile of Test Product at day 2, derived from the administration of anembodiment of an extended release solid dosage form of the presentdisclosure and a reference product.

FIG. 11 illustrates the linear overall profile of the mean measuredplasma concentration versus time profile of Test Product and referenceproduct, derived from the administration of an embodiment of an extendedrelease solid dosage form of the present disclosure and the referenceproduct.

FIG. 12 illustrates the ln-transformed overall profile of the meanmeasured plasma concentration versus time profile of Test Product andreference product, derived from the administration of an embodiment ofan extended release solid dosage form of the present disclosure and thereference product.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION

As used herein the following terms have the definitions set forth below.

“Hydropathy” refers to a scale of solubility characteristics combininghydrophobicity and hydrophilicity of amino acids. More particularly thisterm refers to a sliding scale, similar to a pH scale, which assignsrelative values which represent the relative balance between hydrophobicand hydrophilic components of an amino acid. A typical scale is setforth in Pliska et al., J. Chromatog. 216, 79, 1981, entitled RelativeHydrophobic Character of Amino Acid Side Chains, wherein glycine has avalue of 0, representing a relatively equal balance between hydrophobicand hydrophilic components and may be referred to as relatively‘neutral’, ‘balanced’, ‘slightly hydrophilic’; or ‘weakly hydrophobic’,iso-leucine has a positive value of 1.83 and is strongly hydrophobic,and on the opposite end of the scale, aspartic acid has a negative valueof −2.15 and may be characterized as strongly hydrophilic. Such a scaleand the hydropathy characteristics described herein are well known andunderstood by those skilled in the art.

“Monolithic” refers to tablets that do not require multiple layers,special shapes, osmotic compartments and/or specialized coatings,typically without joints or seams, and are capable of being tableted onmodern high speed tableting equipment.

The term “bimodal” as used herein refers to bimodal drug releaseprofiles (fast release/slow release).

A “serotonin antagonist” or “5-HT₃ receptor antagonist” refers to aclass of medications useful in preventing and relieving nausea andvomiting caused by chemotherapy and anesthesia. It is believed thatserotonin antagonists work by blocking the effects of the chemicalserotonin, which is produced in the brain and the stomach. 5-HT₃receptor antagonists efficacious in treating chemotherapy-induced emesisinclude, but are not limited to, dolasetron, granisetron, ondansetron,palonosetron, tropisetron.

Extended release solid dosage forms are provided. More particularly, thepresent disclosure relates to extended release bimodal solid dosageforms for the prevention of chemotherapy induced nausea and vomiting. Inan embodiment, an extended release solid dosage form includes aninternal portion, wherein the internal portion comprises a first dose ofondansetron; a first coating, wherein the first coating directlyencapsulates the internal portion of the solid dosage form; a drug layercoating, wherein the drug layer coating directly encapsulates the firstcoating, wherein the drug layer coating comprises a second dose ofondansetron, wherein the drug layer coating is at least 4%, by weight,of the solid dosage form, wherein the second dose is equal to at least15%, by weight, of a total dose of the ondansetron in the solid dosageform, and wherein the first dose is equal to the total dose minus thesecond dose; and a second coating, wherein the second coating directlyencapsulates the drug layer coating, wherein the internal portion hassolubility in water of X, wherein the first coating, the drug layercoating, and the second coating have solubility in water of at least Y,and wherein X is less than Y. In an embodiment, the extended releasesolid dosage form is capable of producing a burst of approximately 25%ondansetron, followed by a zero-order release of the remainingondansetron over a period of between 16-20 hours. In an embodiment, theextended release solid dosage form is capable of producing a burst ofapproximately 25% ondansetron, followed by a zero-order release of theremaining ondansetron over a period of between 20-30 hours.

In an embodiment, a solid dosage form of the present invention includesoral dosage forms such as tablets, capsules, caplets, granules. In anembodiment, a solid dosage form of the present invention is a rectaldosage form such as suppository.

Ondansetron

Ondansetron is an effective antiemetic agent that has greatly improvedthe quality of life of patients undergoing chemotherapy. The usual doseadministered to patients ranges between 8 mg, 16 mg, 24 mg or 32 mg perday, administered once a day or in divided doses. Ondansetron displayscentral and/or peripheral action by preferentially blocking theserotonin 5-HT₃ receptors. Ondansetron hydrochloride (HCl) is thedihydrate, the racemic form of ondansetron. Ondansetron has theempirical formula C18H19N30.HCl.2H2O, representing a molecular weight of365.9. Ondansetron HCl dihydrate is a white to off-white powder that issoluble in water and normal saline.

Internal Portion (“Core”) of Solid Dosage Forms of an Embodiment of thePresent Disclosure

As a tablet passes through the human digestive tract, it is subjected topH values ranging from about 1.5 to about 7.4. The saliva of the mouthhas a neutral pH, the stomach has a pH varying from about 1.5-4.0, andthe pH of the intestines carries a pH between about 5.0-7.5. For a drugto approach zero-order release, the drug's dissolution must beindependent of the pH in the surrounding environment. The internalportion (“core”) of a dosage form of the present disclosure may approachzero order delivery of a drug.

Internal Portion—Electrolyte Platform

In an embodiment, the internal portion (“core”) is comprised of ahydrophilic swellable matrix, in which is disposed a pharmaceuticallyactive agent (“API”) and one or more electrolytes. The “electrolytecore” is a slow release (“SR”) formulation. The one or moreelectrolytes, either in combination with the API or another salt uponreaction in an aqueous medium, causes a hardening reaction of thematrix. The rate of outward diffusion is controlled by exposing theinternal portion to an aqueous medium. This in turn causes a hardeningreaction to occur in a time dependent manner from the outer boundariestowards the inner boundaries of the internal portion; the hardenedreaction product, in turn limits outward diffusion of the API as theinward ingress of aqueous medium causes a progressive hardening from theouter boundaries of the internal portion in a direction towards theinner core there.

The internal portion employs the colloidal chemistry phenomenon of“salting-out” to moderate the swelling and erosion kinetics of anon-ionic polymer matrix containing the API and one or moreelectrolytes. The presence of these electrolytic compounds in the formof ionizable salts allows for non-collapsible diffusion channels toform; channelization agents used in the past were not ionizable,therefore, the diffusion channels were unpredictable leading to poorrelease profiles and lack of control. The electrolytes also contributeto a contracting micro-environment within the tablet, whose pH ismediated by the pKa of the electrolyte, thus either enhancing orsuppressing the solubility of the API itself. As the matrix hydrates,the electrolytes and polymer compete for water of hydration with theAPI, resulting in a programmable rate of release. The internal portionis thus capable of zero-order, pH-independent release of an API for upto 24-hours, without regard to the solubility of the API itself.

Through processes of ionic interaction/complexation/molecular and/orself association between a drug and an electrolyte or electrolyte/drugcombinations, homogeneously dispersed in a swellable polymer such ashydroxypropylmethylcellulose (HPMC), modify the dynamics of the matrixswelling rate and erosion of the swellable polymer, in accordance withvariations in an external pH environment ranging from about 1.5-7.0.These interactions result in controlled matrix hardening. Such hardeningis responsible for the control of polymer erosion/dissolution and drugrelease rates. By design, solvent penetrates the periphery of the tabletand a rapid initial interaction between drug and electrolyte embedded inthe polymeric matrix causes immediate hardening of the outer tabletboundary, the rate of hardening consistently decreases toward the centerof the matrix core in a time-dependent manner over a long period of time(e.g. 24 hours).

The differential rate of matrix hardening is the driving principle inthe internal portion, which is dependent on and controlled by the rateof liquid ingress to the internal portion core. With the simultaneoustime-dependent decrease in gel layer integrity, the rate of drugdiffusion decreases. This phenomenon compensates for the increase indiffusion path length and decrease in the surface area of the recedingcore which arises from the swelling property of the polymer. Hence,better controlled, preferably zero order, drug release is achieved. Thedrug release process can be tailored for up to 24 hours. Control of thechanges in core hardness and synchronization of the rubbery/swellingfront and described receding phase boundaries as well as erosion of thedissolution front boundary (i.e. erosion of the tablet periphery)results in controlled drug release, preferably including zero orderkinetics. Optionally, polymer matrix hardening is also easily achievablethrough double salt interaction. This binary salt combination is alsouniformly dispersed in the polymeric matrix, which through ionicinteraction/complexation/molecular and/or self association, increasesthe relative strength and rigidity of the matrix, resulting incontrolled drug release with a similar mechanism to that describedabove.

One hydrophilic matrix material useful in the internal portion is HPMCK4M. This is a nonionic swellable hydrophilic polymer manufactured by“The Dow Chemical Company” under the tradename “Methocel”. HPMC K4M isalso abbreviated as HPMC K4MP, in which the “P” refers to premiumcellulose ether designed for controlled release formulations. The “4” inthe abbreviation suggests that the polymer has a nominal viscosity (2%in water) of 4000. The percent of methoxyl and hydroxypropryl groups are19-24 and 7-12, respectively. In its physical form, HPMC K4M is afree-flowing, off-white powder with a particle size limitation of90%<100 mesh screen. There are other types of HPMC such as K100LVP,K15MP, K100MP, E4MP and E10MP CR with nominal viscosities of 100, 1500,100000, 4000, and 10000 respectively.

Because the internal portion consists of a non-covalently bonded matrix,the manufacturing process is a fundamentally two-step process ofdry-blending and direct compression.

In an embodiment, a salt is dispersed in the matrix at a concentrationin the range of about 50% to about 100% by weight of the polymericmatrix. In an embodiment, the salt is selected from one or two membersof the group consisting of sodium chloride, sodium bicarbonate,potassium bicarbonate, sodium citrate, sodium bisulfate, sodium sulfite,magnesium sulfate, calcium chloride, potassium chloride, and sodiumcarbonate.

It is believed that an interaction between drug and salt forms a complexin the surrounding swellable matrix in a layered fashion because itoccurs in a time-dependent manner as the solvent media for drug releasepenetrates the tablet inwardly. Likewise, because the catalyst for theinitiation of drug release is liquid ingress, so too is the rate of drugrelease controlled by the inwardly progressive hardening of the saltcomplex.

A binary salt system (e.g. calcium chloride and sodium carbonate) mayalso be used in which case the hardening reaction may be a function ofinteraction between the salts. Calcium chloride may be incorporated toform a complex with sodium carbonate. With this combination, thereaction products are insoluble calcium carbonate and soluble channelformer, sodium chloride. Hence the calcium carbonate embeds itself inthe polymer matrix, initiates hardening and slowly dissolves with liquidingress and the subsequent creation of diffusion channels as drugdiffuses out. In a similar way, other binary salt combinations displaytime-dependent “hardening/de-hardening” behavior.

The amount of salt to be used may be determined taking intoconsideration the solubility of the drug, the nature of the polymer andthe required degree of matrix hardening desired. In case of diltiazemhydrochloride in a HPMC matrix, 100 mg of sodium bicarbonate providessuitable matrix hardening for zero order controlled release, while inthe case of the same amount of drug in a different polymer such aspolyethylene oxide, 50 mg of sodium bicarbonate appears to be ideal forthe attainment of controlled zero order release.

The pharmaceutically active ingredient can be selected from the groupconsisting of Aprepitant (Emend), Dexamethasone, Dolasetron (Anzemet),Dronabinol (Marinol), Droperidol (Insapsine), Granisetron (Kytril),Haloperidol (Haldol), Methylprednisolone (Medrol), Metoclopramide(Reglan), Nabilone (Cesamet), Ondansetron (Zofran), Palonosetron(Aloxi), Prochlorperazine (Procomp), and pharmaceutically acceptablesalts thereof, or combinations thereof.

In an embodiment, the internal portion of a solid dosage form of thepresent disclosure is a hydrophilic swellable polymeric matrix havingdispersed within the matrix a pharmaceutically effective amount of atleast one serotonin antagonist whose degree of solubilization issubstantially independent of pH over a pH in the range of pH 1.5 to pH7.5 and an inorganic salt, wherein the inorganic salt is present at aconcentration in the range of 50% to 100% by weight of the polymericmatrix. In an embodiment, the inorganic salt is sodium citrate. In anembodiment, the hydrophilic swellable polymeric matrix ishydroxypropylmethylcellulose or polyethylene oxide.

An internal portion as described above can be prepared by a process asdisclosed in U.S. Pat. No. 6,090,411, which is incorporated herein byreference for the teachings disclosed therein.

Internal Portion—Amino Acid Platform

In an embodiment, the internal portion (“core”) is comprised of ahydrophilic extragranular polymer in which is dispersed a plurality ofgranules of an API, granulated with at least one amino acid, and anintragranular polymer. The “amino acid core” or “AA core” is a slowrelease (“SR”) formulation. The granules are dispersed within ahydrophilic extragranular polymer to form a monolithic matrix. Theextragranular polymer more rapidly hydrates relative to theintragranular polymer. The rapid hydration of the extragranular polymerassists in the approximation of a linear release profile of the drug andfacilitates near 100% dissolution, while extending the duration ofrelease and reducing the burst effect frequently encountered withextended release dosage forms. Although the linear release rate can betailored to fit the needs of each application by selecting polymers fordifferent dissolution rates, as understood by one of ordinary skill inthe art, a release time of 12 to 24 hours is most preferred.

The intragranular polymer is combined with an API, and at least oneamino acid to form granules. The intragranular polymer may be one ormore of the following: polyvinyl acetate, a galactomannan polysaccharidesuch as hydroxypropyl guar, guar gum, locust bean gum, pectin, gumacacia, gum tragacanth, karaya gum, cellulose ethers such ashydroxyproplymethyl cellulose (HPMC), as well as other gums andcellulose ethers to be chosen by one of skill in the art for propertiesconsistent with the teaching of this invention. In an embodiment, theintragranular polymer is a galactomannan polysaccharide such as guar gum(with a viscosity range of 75-6000 cps for a 1% solution at 25° C. inwater and a particle size 10-300 μm).

The intragranular polymer in the internal portion is present in amountsbetween 4% and 45% of the total dosage form weight. The specific type ofintragranular polymer and amount of intragranular polymer used is chosendepending on the desired rate of drug release, viscosity of the polymer,the desired drug load, and the drug solubility. The intragranularpolymer hydrates less rapidly than the extragranular polymer. Therelative difference in hydration rates between the two polymers createsa less viscous intragranular polymer and a more viscous extragranularpolymer. Over time, the difference in viscosity contributes to thecontinuous erosion and disintegration of the solid dosage form.

Amino acids are useful in this embodiment for two primary reasons.First, the amino acids are a factor in determining the viscosity of thepolymers. As noted above, over time the difference in viscosity betweenthe extragranular and intragranular polymers contributes to thecontinuous erosion and disintegration of the core, facilitating about100% release of the drug. Another important aspect of using an aminoacid in the granule is that the hydropathy of the amino acid may beexploited to modulate the solubility and release of a drug.

Thus, the amino acid is selected for hydropathy characteristicsdepending on the solubility characteristics of the active compound. Whenthe compound is at least sparingly water soluble, that is, for example,sparingly soluble, soluble or has a higher level of solubility, asdefined by the United States Pharmacopeia, an amino acid is utilizedwhich has a relatively equal balance between hydrophilic and hydrophobiccomponents, i.e. is neutral or balanced or within close proximity toneutrality, or is relatively more strongly hydrophilic.

For example, dissolution and release of soluble or sparingly solubleionizable drugs such as verapamil HCl can be controlled by the inclusionof one or more amino acids in the granules. Without subscribing to aparticular theory of drug release and dissolution, it is believed thatthe nature of the granulation process is such that as the formulationcomponents come into close molecular contact, granulation reduces theavailable surface area of the particles, thus reducing the initial rateof hydration. In the granulated formulations, there is sufficient timefor the amino acid carboxyl (COOH—) groups and amino groups (NH₂/NH₃₊)to interact with hydroxyl groups on the polymer, thus mediating theswelling, viscosity, and gel properties of the polymer and therebyexerting control on the swelling mediated drug diffusion.Simultaneously, the amino acid carboxyl groups may also interact withsuitable polar substituents on the drug molecule such as secondary ortertiary amines. Furthermore, the hydrophilic and ionic nature of aminoacids results in their extensive hydration in aqueous solution.Consequently, the amino acid promotes erosion, but also competes withboth the polymer and the drug for water uptake necessary for hydrationand dissolution.

However, when the active compound is less than sparingly soluble,including active compounds which are slightly soluble to insoluble, acombination of at least two amino acids is utilized, one of which isstrongly hydrophobic, the other of which is relatively more hydrophilicthan the hydrophobic component, that is about neutral or balanced tostrongly hydrophilic.

The amino acid component of the granules may comprise anypharmaceutically acceptable α-amino or β-amino acids, salts of α- orβ-amino acids, or any combination thereof. Examples of suitable α-aminoacids are glycine, alanine, valine, leucine, iso-leucine, phenylalanine,proline, aspartic acid, glutamic acid, lysine, arginine, histidine,serine, threonine, cysteine, asparagine, and glutamine. An example of aβ-amino acid is β-alanine.

The type of amino acids used in this embodiment of the internal portioncan be described as hydrophilic, hydrophobic, salts of hydrophilic orhydrophobic amino acids, or any combination thereof. Suitablehydrophobic amino acids for use include, but are not limited to,iso-leucine, phenylalanine, leucine, and valine. Further, hydrophilicamino acids, such as glycine, aspartate and glutamate can be used in thegranule. Ultimately, any amino acid, and any amino acid in combinationwith another amino acid, can be employed in the present invention toenhance the solubility of a drug. For a detailed list of amino acidsthat can be used in the present invention and the hydropathy of each,see Albert L. Lehninger et al., Principles of Biochemistry 113 (2nd ed.Worth Publishers 1993).

The type and amount of amino acid may be chosen depending on the desireddrug load, desired rate of drug release, and the solubility of the drug.The amino acid in the dosage form is typically between 4% and 45% of thetotal dosage form weight. However, the amount of amino acid ispreferably between 11% and 29% by weight of the total dosage form.

The granules may optionally be blended with a coating material, forexample magnesium stearate or other hydrophobic derivatives of stearicacid. The amount of coating material used can vary from 1% to 3% of thetotal weight of the dosage form. Normally, magnesium stearate is used tofacilitate processing, for example as a flow aid, but in the presentinvention magnesium stearate has the additional benefit of retardingdissolution, due to the hydrophobic nature of the coating material.Therefore, magnesium stearate can be used to further adjust thesolubility of the dosage form and further retard drug release from thegranules.

To enhance the mechanical properties and/or to influence the drugrelease rate further, the granules may also contain small amounts ofinert pharmaceutical fillers and binders/granulating agents as isconventional to the art. Examples of inert pharmaceutical fillersinclude: lactose, sucrose, maltose, maltodextrins, dextrins, starch,microcrystalline cellulose, fructose, sorbitol, di- and tri-calciumphosphate. Examples of granulating agents/binders include starch,methylcellulose, hydroxy propyl- or hydroxypropylmethyl cellulose,sodium carboxymethyl cellulose, or poly-vinyl pyrrolidone, gum accaciatragacanth and sucrose. Other suitable fillers may also be employed asunderstood by one of skill in the art. Depending on the physical and/orchemical properties of the drug, a wet granulation procedure (usingeither an aqueous or organic granulating fluid) or a dry granulationprocedure (e.g. slugging or roller compaction) can be employed.

After the granulation of the pharmaceutically active compound,intragranular polymer, amino acids, and optionally fillers andhydrophobic coating materials, the granule is then blended with anddispersed within an extragranular polymer.

The extragranular polymer may be one or more of the following:polyethylene oxide, a galactomannan polysaccharide such as hydroxypropylguar, guar gum, locust bean gum, pectin, gum accacia, gum tragacanth,karaya gum, cellulose ethers such as hydroxypropylmethyl cellulose(HPMC), as well as other gums and cellulose ethers to be chosen by oneof skill in the art for properties consistent with the teaching of thisinvention. The extragranular polymer may be a galactomannanpolysaccharide such as guar gum (with a viscosity range of 75-6000 cpsfor a 1% solution at 25° C. in water and a particle size 10-300 μm). Asnoted above the extragranular polymer should hydrate rapidly and achievea high level of viscosity in a shorter period of time relative to theintragranular polymer.

The difference in hydration rates between the extragranular polymer andintragranular polymer is achieved by three principle means, (1) bychoosing polymers based on differences in particle size, (2) by choosingpolymers based on differences in molecular weight and chemicalcomposition and (3) by choosing polymers based on a combination of (1)and (2). Although this disclosure focuses primarily on polymers chosenfor differences in particle size, it is possible to achieve the resultsof this invention by using an intragranular polymer with a differentmolecular weight and/or chemical composition than the extragranularpolymer. For example, polyethylene oxide may be used as theintragranular polymer and guar gum as the extragranular polymer.

Particle size is another characteristic of commercial guar gum becausecoarser particles ensure rapid dispersion, while finer particles areideal for fast hydration. Therefore, in order to achieve the desiredresult of the present invention. In an embodiment, the finer particlesare used for the extragranular polymer and less fine particles are usedfor the intragranular polymer particles. The brochure by HERCULESIncorporated, entitled “Supercol® Guar Gum, 1997” contains the typicalproperties of guar gum of different grades and particles sizes. Otherrapidly hydrating extragranular polymers which may be used include:polyethylene oxide (PEO), cellulose ethers and polysaccharides such ashydroxypropyl guar, pectin, gum accacia and tragacanth, karaya gum,mixtures of the aforementioned polymers and any other polymers to bechosen by one of skill in the art for properties consistent with theteaching of this invention. The amounts and the types of extragranularpolymer are chosen depending on the desired drug load, rate of drugrelease and drug solubility. A range of about 4-47% (by total tabletweight) of extragranular polymer has been found to be feasible, but arange of about 15%-47% is particularly preferred.

A therapeutic amount of an API, for example up to about 75% of the totaldosage form weight, can be included in the internal portion. With thisdrug load, the internal portion approximates a linear release profile,with a minimal, or elimination of, burst effect. However, if desired bya skilled artisan, the extragranular polymer may contain additionalamounts of the pharmaceutically active compound to achieve more rapiddrug release or an induced burst effect, as well as contain amino acidsto mediate dissolution of the pharmaceutically active compound, asdescribed above.

The tableted oral extended release dosage form optionally may be coatedwith polymers, plasticizers, opacifiers, and colourants as isconventional in the art.

In an embodiment, the internal portion of a solid dosage form of thepresent disclosure is (1) a plurality of granules comprising (a) atleast one serotonin antagonist; (b) at least one amino acid; and (c) anintragranular polymer; the intragranular polymer comprising 4% to 45% ofthe total dosage form by weight and, (2) a hydrophilic extragranularpolymer in which the granules are dispersed, the extragranular polymercomprising 4% to 47% of the total dosage form by weight and being morerapidly hydrating than the intragranular polymer, wherein the amino acidis selected for hydropathy characteristics depending on solubilitycharacteristics of the at least one serotonin antagonist and comprises11% to 29% of the total dosage form by weight. In an embodiment, whenthe at least one serotonin antagonist is at least sparingly soluble inwater, the amino acid has a relatively equal balance between hydrophobicand hydrophilic components or is relatively more hydrophilic. In anembodiment, when the at least one serotonin antagonist is less thansparingly soluble in water, the amino acid is a combination of at leasttwo amino acids, one of which is moderately or strongly hydrophobic, theother of which is relatively more hydrophilic. In an embodiment, theintragranular polymer comprises at least one of the following: polyvinylacetate, a galactomannan polysaccharide selected from the groupconsisting of hydroxypropyl guar, guar gum, locust bean gum, pectin, gumaccacia, tragacanth, karaya gum, or cellulose ethers. In an embodiment,the amino acid is selected from the group consisting of: a) α-aminoacids b) β-amino acids c) a combination of α- and β-amino acids. In anembodiment, the α-amino acid is at least one member selected from thegroup consisting of glycine, alanine, valine, leucine, iso-leucine,phenylalanine, proline, aspartic acid, glutamic acid, lysine, arginine,histidine, serine, threonine, cysteine, asparagine and glutamine. In anembodiment, the combination of α and β amino acids comprises β-alanineand at least one α-amino acid selected from the group consisting ofglycine, alanine, valine, leucine, iso-leucine, phenylalanine, proline,aspartic acid, glutamic acid, lysine, arginine, histidine, serine,threonine, cysteine, asparagine, and glutamine. In an embodiment, theamino acid is selected from the group consisting of: a) a balanced aminoacid having a relatively equal balance between hydrophobic andhydrophilic components or a relatively more hydrophilic amino acid, orb) a combination of (i) a balanced amino acid or a relatively morehydrophilic amino acid and (ii) a hydrophobic amino acid. In anembodiment, the balanced amino acid comprises glycine. In an embodiment,the internal portion comprises glycine and a hydrophobic amino acidselected from iso-leucine, valine, and phenylalanine. In an embodiment,the plurality of granules are blended with a hydrophobic coatingmaterial. In an embodiment, the hydrophobic coating material ismagnesium stearate. In an embodiment, the hydrophobic coating materialis 1% to 3% of the total dosage form weight.

An internal portion as described above can be prepared by a process asdisclosed in U.S. Pat. No. 6,517,868, which is incorporated herein byreference for the teachings disclosed therein.

First and Second Coatings

The first coating and the second coating of an extended release bimodalsolid dosage form of the present disclosure are non-functional coatingsthat act as processing aids. The first coating and the second coating donot substantially affect the release of the API from the dosage form. Inan embodiment, the first and the second coating comprise a hydrophilicmaterial. In an embodiment, the hydrophilic material is hypromellose. Inan embodiment, the hypromellose is Methocel E5. In an embodiment, thefirst and the second coating further comprise the coating additiveplasACRYL™, an aqueous emulsion of glyceryl monostearate and triethylcitrate (developed by Emerson Resources, Inc. of Norristown, Pa., USA).In an embodiment, the PlasACRYL™ used in the first and second coatingsis T20 grade. In an embodiment, the PlasACRYL™ T20 is a 20% aqueoussuspension, containing an anti-tacking agent, a plasticizer and astabilizer. Hypromellose is a pH independent non-ionic polymer formed bypartial substitution with O-methylated and O-(2-hydroxypropylated)groups. The grades of hypromellose can vary upon extent to substitutionwhich affects the viscosity. HPMC K4M Premium exhibits a viscosity of3550 mPas, while HPMC E5 premium LV is a low viscosity grade polymerhaving a viscosity of 5 mPas. Hypromellose is soluble in cold water andforms a colloidal viscous liquid.

Drug Layer Overcoat

The drug layer overcoat of an extended release solid dosage form of thepresent disclosure is an immediate release (“IR”) drug layer. In anembodiment, the drug layer overcoat is sufficiently designed to yield aburst of about 25% API, which, when the solid dosage form is ingestedorally, would result in about 25% API being released in the stomach. Inan embodiment, the drug layer overcoat, or immediate release drug layer,comprises ondansetron hydrochloride, hypromellose and plasACRYL™. In anembodiment, the hypromellose used in the IR layer is Methocel E5.

Additional Layers—Enteric Coating

In an embodiment, an extended release solid dosage form of the presentdisclosure further includes an enteric coating. In an embodiment, anenteric coating layer is positioned between the first coating and thedrug layer overcoat. In an embodiment, the enteric coating layer isEUDRAGIT® L30D-55. In an embodiment, the enteric coating layer isEUDRAGIT® FS 30 D. In an embodiment, the enteric coating layer isSURETERIC®.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the described invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

EXAMPLES Example 1—Manufacture of 18 mg Ondansetron Internal Cores

TABLE 1 Ondansetron Internal Core, 18 mg; Amino Acid core (“AA core”)Actual Item Ingredients % w/w mg/tablet g/batch 1 Ondansetron HCl 3.83  20.2 † 298.7* 2 Glycine, USP 18.96 100 1327.01 3 Hypromelose, USP18.96 100 1327.01 (Methocel K15M Premium CR) 4 MicrocrystallineCellulose, 19.84  104.7 1358.2* NF (Avicel ® PH-102) 5 Hypromelose, USP(Methocel 37.91 200 2654.03 K100 Premium LV) 6 Purified Water, USP1750.0 7 Magnesium Stearate, NF 0.50   2.6 35.0 Totals 100.00  527.57000.00 *adjusted based on API potency: MCC reduced to compensate † 20.2mg of Ondansetron HCl is equivalent to 18 mg of Ondansetron

The amino acid formulation (“AA core”) was manufactured using low shearwet granulation. The Avicel® PH-102 microcrystalline cellulose,ondansetron HCl, glycine and HPMC K15M were mixed in a 1 cu ft V-blenderfor 10 minutes, discharged and delumped using a Comil equipped with a 20mesh screen. The pre-blend was then granulated in the Hobart D300 byadding water to the blend while mixing. After the water was added thematerial was mixed for an additional 2 minutes. The material wasgranulated adequately but not overly wet, therefore no additional waterwas added. The wet mass was screened through an 8 mesh screen then ovendried. The dried granulation was milled using a Comil with an 18meshscreen, blended with the extragranular HPMC K100LV and lubricant.Compression of the final blend was conducted on a 36-station Kikusuipress using the 0.32″×0.58″ modified oval tooling.

TABLE 2 Ondansetron Internal Portion, 18 mg; Electrolyte core(“Electrolyte core”) Item Ingredients % w/w mg/tablet g/batch 1Ondansetron HCl 5.39   20.20 † 601.10* 2 Hypromelose, USP (Methocel26.70 100.00 2670.23 K4M Premium CR) 3 Sodium Citrate Anhydrous, USP13.35  50.00 1335.11 (fine granular) 4 Microcrystalline Cellulose, NF54.02 202.30 5340.2* (Avicel ® PH-102) 5 Magnesium Stearate, NF 0.53 2.00 53.40 (vegetable grade) Totals 100.00 374.50 10000.00 *adjustedbased on API potency: MCC reduced to compensate † 20.2 mg of OndansetronHCl is equivalent to 18 mg of Ondansetron

The electrolyte formulation (“Electrolyte core”) was manufactured byblending and compression. All the materials were screened separatelythrough a 30 mesh hand screen, charged into the V-blender and mixed for15 minutes then lubricated. Compression was conducted on a 36-stationKikusui press using the 0.28″×0.50″ modified oval tooling.

Example 2—First and Second Seal Coatings; Optional Enteric Coating

TABLE 3 Seal Coat Formula (sub coating and top coat) Item Ingredients %w/w g/batch* 1 Hypromellose (Methocel E5) 6.00 109.2 2 PlasACRYL ™T200.60 10.92 3 Purified Water 93.40 1699.88 Total 100.0 1820.00 *batchsize is for one seal coating, with ~30% overage

TABLE 4 Enteric Coating Formula item Ingredients % w/w g/batch * 1EUDRAGIT ® L30D-55 (30% 71.22 1365.68 dispersion) 2 PlasACRYL ™ T20 (20%emulsion) 10.68 204.13 3 Triethyl citrate 1.08 21.24 4 Purified Water17.02 768.86 Total 100.00 2359.91 * batch size includes 30% overage

The seal coating solution was manufactured by dissolving the Methocel E5in water, then adding the PlasACRYL™. The enteric coating suspension wasmanufactured by mixing the water, triethyl citrate and PlasACRYL™. TheEUDRAGIT® dispersion was added; the suspension was mixed for 30 minutesthen screened through a 60 mesh screen. The active suspension wasmanufactured by first dissolving the Methocel E5 in water, andseparately dispersing the ondansetron in water and homogenizing. TheMethocel solution was then added to the drug suspension, and thePlasACRYL™ was added.

Example 3—Drug Layer Overcoat

TABLE 5 Drug layer coating Formulas 1 2 3 Ingredients % w/w g/batch*g/batch* g/batch* 1 Ondensatron HCl 2.40 65.82 87.76 83.37 2Hypromellose 3.60 98.72 131.63 0.13 (Methocel E5) USP 3 PlasACRYL ™ (20%0.90 24.68 32.91 31.26 emulsion) 4 Purified Water 93.10 2553.13 3404.183233.97 Total 100.00 2742.35 3656.47 3473.65 *Batch sizes include an 18%overage to account for manufacturing losses

The tablets were coated with the required coatings as listed in Tables6-8. Weight gain was monitored by measuring the weight of 50 tabletsevery 10 minutes. Due to equipment availability, the 1^(st) two batcheswere coated using the R&D tablet coater (O'Hara LabMX). The 3^(rd) batchwas manufactured using the cGMP equipment which will be used for the CTMmanufactures.

TABLE 6 Coating Parameters; Product 1 AA core O'Hara LabMX Initial sealcoat IR coat Final topcoat Starting charge (kg) 3.956 3.953 4.058 Inlettemp (° C.) 61.8-62.4 59.9-62.5 61.0-63.1 Outlet temp (° C.) 42.5-44.143.5-44.1 42.5-45.5 Pan speed (rpm) 12 12 12 Spray rate (g/min)25.3-27.0 24.2-26.5 22.1-27.5 Atomization 25 25 25 pressure (psi) Inletairflow (cfm) 200 200 200 Final weight gain 2.05% 20.9 mg/tablet 2.09%Coating efficiency 100%

TABLE 7 Coating Parameters; Product 2 Electrolyte core O'Hara LabMXInitial seal coat IR coat Final topcoat Starting charge 3.745 3.8143.990 Inlet temp (° C.) 60.5-62.2 60.0-61.4 61.0-62.8 Outlet temp (° C.)42.4-43.8 42.2-43.7 42.2-44.0 Pan speed (rpm) 12 12 12 Spray rate(g/min) 25.1-26.8 25.8-27.6 24.2-30.5 Atomization 25 25 25 pressure(psi) Inlet airflow (cfm) 200 200 200 Final weight gain 2.12% (79.4 g)20.2 mg/tablet 2.23% Coating efficiency 93%

TABLE 8 Coating Parameters; Product 3 Electrolyte core, Enteric coat +Drug overcoat Initial Enteric Drug Final Driam Driacoater seal coat coatovercoat topcoat Starting charge 3.558 3.627 3.991 4.143 Inlet temp (°C.) 44.0-60.0 42-47 45-47 44-48 Outlet temp (° C.) 43-48 41-46 42-4441-45 Pan speed (rpm) 12 12 12 12 Spray rate (g/min) 22.7-24.6 16.7-19.623.1-27.3 24.7-27.5 Atomization 35 30-35 30 30 pressure (psi) Inletairflow (cfm) 300 300 300 300 Final weight gain 2.50% 10.24% 19.5mg/tablet 2.33% Coating efficiency 84.5%

TABLE 9 Overall Batches Product # 1 2 3 Mg/ g/ Mg/ g/ Mg/ g/ Ingredient% w/w tablet batch % w/w tablet batch % w/w tablet batch Ondansetron CDT92.81 527.50 3956.25 tablet, 18 mg Ondansetron CDT 91.53 374.50 3745.0083.57 374.50 3557.75 tablet, 18 mg Hypromellose seal 1.86 10.55 79.131.83 7.49 74.90 1.67 7.49 71.16 coat Enteric coating 8.52 38.20 362.90(Eudragit ®) Ondansetron 3.37 19.15* 143.63 4.68 19.15* 191.50 4.2719.15* 181.93 drug overcoat Hypromellose seal 1.96 11.14 83.58 1.96 8.0280.23 1.96 8.79 83.47 coat Total 100.00 568.34 4262.58 100.00 409.164091.63 100.00 448.13 4257.20

Example 4—Dissolution Profile

TABLE 10 Dissolution (Ondansetron Bimodal Release Tablets, 24 mg)Product 1 Product 2 Product 3 Amino acid Electrolyte Electrolyte Tabletstrength (mg) 24 24 24 Apparatus II (paddle) II (paddle) II (paddle)Sinker Japanese basket Japanese basket Japanese basket # units  6  6  6Speed (rpm) 50 50 50 Time Dissolution point Mean % % Mean % % Mean % %media (hrs) dissolved RSD dissolved RSD dissolved RSD water 0.5 25.8 9.925.3 6.7 0.1N HCl 25.2 4.8 2 38 5.5 41.4 4 25.8 4.9 3 45.1 5.4 51.1 3.4pH 6.8 33.8 7.8 4 50.6 4.9 58.1 3.4 phosphate 44 4.9 6 60 4.1 69.7 3.8buffer 61.4 5.4 9 71.5 3.9 82.7 4.2 79.7 2.7 12 79.5 3.6 93.1 4.1 89.52.5 15 84.6 3.4 99.2 4.1 95.8 3.6 18 88 3.4 102.5 3.8 98.6 3.1 21 90.83.3 103.8 3.7 100 3.6 24 93.1 3.1 104.6 3.6 101.6 3.4Table 10 in conjunction with FIG. 1 and FIG. 2 show the dissolutionprofile for Products 1, 2 and 3. For product 1, there was an initial 25%burst, followed by a sustained release over 24 hours. For product 2,there was an initial 25% burst, followed by a sustained release over 24hours. For product 3, there was initial 25% burst, followed by a lag inrelease while in acid.

Example 5—Manufacture of Ondansetron Internal Electrolyte Core

Ondansetron HCl tablet cores were prepared through dry-blend and directcompression. Details of the formulation ingredients are depicted inTables 11 and 12. The dissolution profile (assuming enteric coating and6 mg immediate release drug coating) for this formula is shown in FIG.3.

TABLE 11 Ondansetron Electrolyte 11- tablet core Ondansetron HClElectrolyte 11 % w/w mg/dosage Ondansetron HCl 5.30% 22.5 sodium citrate11.78% 50 HPMC K4M 23.56% 100 MCC 47.11% 200 mg stearate 0.47% 2 Total374.5

TABLE 12 22.5 mg Ondansetron HCl Formulation 11 Raw Material PurposeManufacturer Lot Number w/w % mg/dosage Ondansetron HCl API DRL ON01 3105  5.30% 22.5 HPMC K4M Polymer Colorcon WP193724 23.56% 100.00 SodiumCitrate Electrolyte Gadot Biochemical Ind. 48010004 11.78% 50.00 AvicelMCC PH 102 Flow Agent FMC Biopolymer P208819629 47.11% 200.00 MgStearate Lubricant Mallinckrodt E17591  0.47% 2.00 Total  100% 374.5

Example 6—Dissolution Profile

In vitro dissolution was performed with physiologically relevant mediawithin a pH range of 1.2 to 7.2, approximating levels found through theGI tract. Due to differences in solubility at various pH of theondansetron HCl API, absorbance max was used to calculate dissolutionrelease rather than the calibration curve created with the API in water.Dissolution testing results for media: pH1.2, 4.5, 6.8, 7.2 and diH₂Ocan be seen in FIG. 4.

Example 7—In Vivo Testing of Solid Dosage Forms

A single center, randomized, laboratory-blinded, 4-period, 4-sequence,crossover design study was carried out in healthy male and femalesubjects. The following investigational products were to be administeredunder fasting conditions:

-   -   Test-1: 1× Ondansetron 24 mg bimodal tablet (amino acid core)        Batch no.: 19401.001A    -   Test-2: 1× Ondansetron 24 mg bimodal tablet (electrolyte core)        Batch no.: 19404.001A    -   Test-3: 1× Ondansetron 24 mg bimodal tablet (enteric coated        electrolyte core) Batch no.: 19403.001A    -   Reference: 3×Zofran® 8 mg tablets (1×8 mg tablet administered        three-times daily, at 8-hour intervals: in the morning following        a 10-hour overnight fast, in the afternoon and in the evening)

The products were to be administered to 28 healthy male and femalesubjects according to Table 13.

Period 1 Period 2 Period 3 Period 4 Sequence 1 (n = 7) Test-1 ReferenceTest-2 Test-3 Sequence 2 (n = 7) Test-2 Test-1 Test-3 Reference Sequence3 (n = 7) Test-3 Test-2 Reference Test-1 Sequence 4 (n = 7) ReferenceTest-3 Test-1 Test-2

Selection of Doses in the Study

The dose was chosen to achieve similar exposure as with the marketedimmediate-release formulation (Zofran® 8 mg) when administeredthree-time daily.

Selection and Timing of Dose for Each Subject

Subjects fasted overnight for at least 10 hours prior to morning drugadministration.

Tests 1-3

-   -   A single dose of the assigned Test formulation was administered        orally with approximately 240 mL of water at ambient        temperature, starting at 07:30, to one subject per minute.

Reference

-   -   The assigned Reference formulation was administered orally        (three-times daily, at 8-hour intervals) with approximately 240        mL of water at ambient temperature, starting at 07:30, to one        subject per minute. Subsequent drug administrations took place        in the afternoon and in the evening at 15:30 and 23:30,        respectively.

Fasting continued for at least 4 hours following morning drugadministration, after which a standardized lunch was served. The lunchwas to be completed no later than 5 hours following morning drugadministration. All meals were served at appropriate times thereafter,but not before 9 hours after morning drug administration. The supper wasnot to be served before 11 hours after the morning drug administrationand was to be completed no later than 13 hours following morning drugadministration. Furthermore, the light snack was to be completed nolater than 13 hours after the morning drug administration. Water wasallowed ad libitum until 1 hour pre-dose and beginning 1 hour after eachdrug administration.

Efficacy and Safety Measurements Assessed and Flow Chart PharmacokineticAssessments

Blood samples for pharmacokinetic measurements were collected prior toand up to 32 hours (serial sampling) after each morning drugadministration. The direct measurements of this study were the plasmaconcentrations of ondansetron. These concentrations were obtained byanalysis of the plasma derived from the blood samples drawn during thisstudy. The total volume of blood collected per subject (639 mL for malesand 653 mL for females) is considered to have a negligible or no impacton the pharmacokinetic profiles of the drugs and the assessment ofbioequivalence. Furthermore, it is considered to have a negligibleimpact on subjects' safety.

Drug Concentration Measurements

Tests 1-3 (21 Blood Samples):

-   -   The first blood sample of each period, i.e. the blank plasma        sample, was collected prior to drug administration while the        others were collected 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5,        6, 7, 8, 9, 10, 12, 16, 20, 24 and 32 hours after drug        administration in one tube of 6 mL (K2 EDTA Vacutainers)

Reference (33 Blood Samples):

-   -   The first blood sample of each period, i.e. the blank plasma        sample, was collected prior to the morning drug administration        while the others were collected 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4,        6, 8, 8.25, 8.5, 9, 9.5, 10, 10.5, 11, 12, 14, 16, 16.25, 16.5,        17, 17.5, 18, 18.5, 19, 20, 22, 24, 28 and 32 hours following        the morning drug administration in one tube of 6 mL (K2 EDTA        Vacutainers). Samples at 8-hour and 16-hour were collected        within 5 minutes before the drug administration (the afternoon        and evening administrations).

Ondansetron—Test-1 vs Reference

Twenty-six (26) subjects were included in the comparison between Test-1and Reference. A summary of the pharmacokinetic parameters and thestandards for comparative bioavailability are presented in Tables 14 and15. The mean measured plasma concentration versus time profile, derivedfrom the administration of the Test-1 and Reference products, isdepicted in FIG. 5, whereas the ln-transformed mean concentration versustime profile is depicted in FIG. 6.

TABLE 14 Summary of Main Study Results - Ondansetron - Test-1 vsReference TEST-1 REFERENCE PARAMETER MEAN C.V. (%) MEAN C.V. (%) C_(max)(ng/mL) 50.669 30.3 50.731 30.5 ln (C_(max)) 3.8742 8.8 3.8835 7.7T_(max) (hours) ^(§) 3.50 23.6 17.50 45.7 AUC_(T) (ng · h/mL) 659.09834.5 854.517 37.4 ln (AUC_(T)) 6.4337 5.4 6.6897 5.3 AUC_(∞) (ng · h/mL)795.397 43.3 946.030 43.5 ln (AUC_(∞)) 6.5921 6.5 6.7741 5.8 AUC_(T/∞)(%) 84.61 12.2 92.07 5.8 K_(el) (hours⁻¹) 0.0671 29.8 0.1391 26.7T_(1/2el) (hours) 11.72 46.3 5.40 31.5 AUC₀₋₂₄ (ng · h/mL) 577.151 32.6720.455 33.6 C₂₄ (ng/mL) 12.134 58.3 26.115 50.6 ^(§) For T_(max), themedian is presented

TABLE 15 Comparison of Results with Standards for Bioequivalence -Ondansetron - Test-1 vs Reference INTRA- 90% CONFIDENCE SUBJECTGEOMETRIC LSMEANS * RATIO LIMITS (%) PARAMETER C.V. (%) TEST-1 REFERENCE(%) LOWER UPPER C_(max) 14.0 48.222 48.685 99.05 92.89 105.62 AUC_(T)11.3 625.797 807.106 77.54 73.60 81.68 AUC_(∞) 14.3 738.123 879.24783.95 78.46 89.82 * units are ng/mL for C_(max) and ng · h/mL forAUC_(T) and AUC_(∞)

The number of subjects included in the statistical analysis of theseparameters was n=24 for the Test-1 and n=26 for the Reference. The meanC_(max) were respectively, 50.669 ng/mL and 50.731 ng/mL for the Test-1and Reference formulations. The Test-1 to Reference C_(max) ratio ofgeometric LSmeans was 99.05% (90% CI: 92.89 to 105.62%). This resultthus demonstrates that the ratio and corresponding 90% confidenceinterval of the relative C_(max) geometric LSmeans of the Test-1 toReference formulation are within the pre-specified 80.00 to 125.00%range. The median T_(max) was 3.50 and 17.50 hours for the Test-1 andReference formulations, respectively. The mean AUC_(T) wererespectively, 659.098 ng·h/mL and 854.517 ng·h/mL for the Test-1 andReference formulations. The Test-1 to Reference AUC_(T) ratio ofgeometric LSmeans was 77.54% (90% CI: 73.60 to 81.68%). This result thusdemonstrates that the ratio and corresponding 90% confidence interval ofthe relative AUC_(T) geometric LSmeans of the Test-1 to Referenceformulation are outside the pre-specified 80.00 to 125.00% range. Themean Kei was 0.0671 hours⁻¹ for the Test-1 formulation and 0.1391hours⁻¹ for the Reference formulation. The mean T_(1/2el) value was11.72 and 5.40 hours, for the Test-1 and Reference formulations,respectively. The mean AUC_(∞) were respectively, 795.397 ng·h/mL and946.030 ng·h/mL for the Test-1 and Reference formulations. The Test-1 toReference AUC_(∞) ratio of geometric LSmeans was 83.95% (90% CI: 78.46to 89.82%). This result thus demonstrates that the 90% confidenceinterval of the relative AUC_(∞) geometric LSmeans of the Test-1 toReference formulation is outside the pre-specified 80.00 to 125.00%range. The mean AUC_(T) over AUC_(∞) individual ratio (AUC_(T/∞)) wererespectively, 84.61% and 92.07% for the Test-1 and Referenceformulations.

Ondansetron—Test-2 vs Reference

Twenty-six (26) subjects were included in the comparison between Test-2and Reference. A summary of the pharmacokinetic parameters and thestandards for comparative bioavailability are presented in Tables 16 and17. The mean measured plasma concentration versus time profile, derivedfrom the administration of the Test-2 and Reference products, isdepicted in FIG. 5, whereas the ln-transformed mean concentration versustime profile is depicted in FIG. 6.

TABLE 16 Summary of Main Study Results - Ondansetron - Test-2 vsReference TEST-2 REFERENCE PARAMETER MEAN C.V. (%) MEAN C.V. (%) C_(max)(ng/mL) 55.718 24.0 50.731 30.5 ln (C_(max)) 3.9889 6.7 3.8835 7.7T_(max) (hours) ^(§) 4.00 13.6 17.50 45.7 AUC_(T) (ng · h/mL) 730.19931.7 854.517 37.4 ln (AUC_(T)) 6.5477 4.7 6.6897 5.3 AUC_(∞) (ng · h/mL)847.660 37.7 946.030 43.5 ln (AUC_(∞)) 6.6836 5.2 6.7741 5.8 AUC_(T/∞)(%) 87.44 5.9 92.07 5.8 K_(el) (hours⁻¹) 0.0676 23.0 0.1391 26.7T_(1/2el) (hours) 10.84 25.8 5.40 31.5 AUC₀₋₂₄ (ng · h/mL) 653.663 29.5720.455 33.6 C₂₄ (ng/mL) 12.088 52.4 26.115 50.6 ^(§) For T_(max), themedian is presented

TABLE 17 Comparison of Results with Standards for Bioequivalence -Ondansetron - Test-2 vs Reference INTRA- 90% CONFIDENCE SUBJECTGEOMETRIC LSMEANS * RATIO LIMITS (%) PARAMETER C.V. (%) TEST-2 REFERENCE(%) LOWER UPPER C_(max) 14.0 54.008 48.685 110.93 104.03 118.30 AUC_(T)11.3 700.467 807.106 86.79 82.38 91.43 AUC_(∞) 14.3 803.436 879.24791.38 85.57 97.58 * units are ng/mL for C_(max) and ng · h/mL forAUC_(T) and AUC_(∞)

The mean C_(max) were respectively, 55.718 ng/mL and 50.731 ng/mL forthe Test-2 and Reference formulations. The Test-2 to Reference C_(max)ratio of geometric LSmeans was 110.93% (90% CI: 104.03 to 118.30%). Thisresult thus demonstrates that the ratio and corresponding 90% confidenceinterval of the relative C_(max) geometric LSmeans of the Test-2 toReference formulation are within the pre-specified 80.00 to 125.00%range. The median T_(max) was 4.00 and 17.50 hours for the Test-2 andReference formulations, respectively. The mean AUC_(T) wererespectively, 730.199 ng·h/mL and 854.517 ng·h/mL for the Test-2 andReference formulations. The Test-2 to Reference AUC_(T) ratio ofgeometric LSmeans was 86.79% (90% CI: 82.38 to 91.43%). This result thusdemonstrates that the ratio and corresponding 90% confidence interval ofthe relative AUC_(T) geometric LSmeans of the Test-2 to Referenceformulation are within the pre-specified 80.00 to 125.00% range. Themean Kei was 0.0676 hours⁻¹ for the Test-2 formulation and 0.1391hours⁻¹ for the Reference formulation. The mean T_(1/2el) value was10.84 and 5.40 hours, for the Test-2 and Reference formulations,respectively. The mean AUC_(∞) were respectively, 847.660 ng·h/mL and946.030 ng·h/mL for the Test-2 and Reference formulations. The Test-2 toReference AUC_(∞) ratio of geometric LSmeans was 91.38% (90% CI: 85.57to 97.58%). This result thus demonstrates that the ratio andcorresponding 90% confidence interval of the relative AUC_(∞) geometricLSmeans of the Test-2 to Reference formulation are within thepre-specified 80.00 to 125.00% range. The mean AUC_(T) over AUC_(∞)individual ratio (AUC_(T/∞)) were respectively, 87.44% and 92.07% forthe Test and Reference formulations.

Ondansetron—Test-3 vs Reference

Twenty-five (25) observations were included for the Test-3 and 26observations were included for the Reference. A summary of thepharmacokinetic parameters and the standards for comparativebioavailability are presented in Tables 18 and 19. The mean measuredplasma concentration versus time profile, derived from theadministration of the Test-3 and Reference products, is depicted in FIG.5, whereas the ln-transformed mean concentration versus time profile isdepicted in FIG. 6.

TABLE 18 Summary of Main Study Results - Ondansetron - Test-3 vsReference TEST-3 REFERENCE PARAMETER MEAN C.V. (%) MEAN C.V. (%) C_(max)(ng/mL) 32.958 28.6 50.731 30.5 ln (C_(max)) 3.4514 9.1 3.8835 7.7T_(max) (hours) ^(§) 5.00 52.2 17.50 45.7 AUC_(T) (ng · h/mL) 646.61134.6 854.517 37.4 ln (AUC_(T)) 6.4122 5.6 6.6897 5.3 AUC_(∞) (ng · h/mL)830.321 47.2 946.030 43.5 ln (AUC_(∞)) 6.6320 6.3 6.7741 5.8 AUC_(T/∞)(%) 80.15 13.7 92.07 5.8 K_(el) (hours⁻¹) 0.0640 38.3 0.1391 26.7T_(1/2el) (hours) 12.73 44.2 5.40 31.5 AUC₀₋₂₄ (ng · h/mL) 546.657 32.9720.455 33.6 C₂₄ (ng/mL) 15.553 50.8 26.115 50.6 ^(§) For T_(max), themedian is presented

TABLE 19 Comparison of Results with Standards for Bioequivalence -Ondansetron - Test-3 vs Reference INTRA- 90% CONFIDENCE SUBJECTGEOMETRIC LSMEANS * RATIO LIMITS (%) PARAMETER C.V. (%) TEST-3 REFERENCE(%) LOWER UPPER C_(max) 14.0 31.973 48.685 65.67 61.54 70.09 AUC_(T)11.3 617.172 807.106 76.47 72.54 80.61 AUC_(∞) 14.3 777.120 879.24788.38 82.53 94.65 * units are ng/mL for C_(max) and ng · h/mL forAUC_(T) and AUC_(∞)

The number of subjects included in the statistical analysis of theseparameters was n=23 for the Test-3 and n=26 for the Reference. The meanC_(max) were respectively, 32.958 ng/mL and 50.731 ng/mL for the Test-3and Reference formulations. The Test-3 to Reference C_(max) ratio ofgeometric LSmeans was 65.67% (90% CI: 61.54 to 70.09%). This result thusdemonstrates that the ratio and corresponding 90% confidence interval ofthe relative C_(max) geometric LSmeans of the Test-3 to Referenceformulation are outside the pre-specified 80.00 to 125.00% range. Themedian T_(max) was 5.00 and 17.50 hours for the Test-3 and Referenceformulations, respectively. The mean AUC_(T) were respectively, 646.611ng·h/mL and 854.517 ng·h/mL for the Test-3 and Reference formulations.The Test-3 to Reference AUC_(T) ratio of geometric LSmeans was 76.47%(90% CI: 72.54 to 80.61%). This result thus demonstrates that the ratioand corresponding 90% confidence interval of the relative AUC_(T)geometric LSmeans of the Test-3 to Reference formulation are outside thepre-specified 80.00 to 125.00% range. The mean Kei was 0.0640 hours' forthe Test-3 formulation and 0.1391 hours' for the Reference formulation.The mean T_(1/2el) value was 12.73 and 5.40 hours, for the Test-3 andReference formulations, respectively. The mean AUC_(∞) wererespectively, 830.321 ng·h/mL and 946.030 ng·h/mL for the Test-3 andReference formulations. The Test-3 to Reference AUC_(∞) ratio ofgeometric LSmeans was 88.38% (90% CI: 82.53 to 94.65%). This result thusdemonstrates that the ratio and corresponding 90% confidence interval ofthe relative AUC_(∞) geometric LSmeans of the Test-3 to Referenceformulation are within the pre-specified 80.00 to 125.00% range. Themean AUC_(T) over AUC_(∞) individual ratio (AUC_(T/∞)) wererespectively, 80.15% and 92.07% for the Test-3 and Referenceformulations.

Example 8—3-Arm Crossover Comparative Bioavailability Study of SolidDosage Forms

3-arm crossover comparative bioavailability study of five day dosing ofsolid dosage forms of the present invention once daily versus two daydosing of twice daily ondansetron 8 mg immediate-release tablets versusa single dose of ondansetron 24 mg immediate-release tablets in HealthyMale and Female Volunteers/Fasting State

Objectives:

The primary objective of this study was to compare the relativebioavailability and peak and trough concentrations between two FDAapproved regimens of commercially available ondansetron 8 mgimmediate-release tablet (twice daily Zofran® 8 mg regimen administeredfor two days and a single dose of Zofran® 24 mg regimen administered asthree Zofran® 8 mg tablets taken together) and the Test Product ofondansetron 24 mg extended-release tablet of the present invention(administered once daily).

Secondary Objectives of the Study were:

-   -   1. To assess the accumulation of ondansetron in the plasma after        dosing with the Test Product for five consecutive daily doses,        under fasting conditions    -   2. To assess the safety and tolerability of the extended-release        formulation on healthy volunteers.

Methodology:

Single center, randomized, open-label, 3-period, 3-sequence, crossoverdesign.

Number of Subjects (Planned and Analyzed):

-   Planned for inclusion: 18-   Included: 18-   Drop-outs: 0-   Analyzed: 18-   Considered in the pharmacokinetic and statistical analysis: 18-   Considered in the safety analysis: 18

Diagnosis and Main Criteria of Inclusion:

Male and female volunteers, non- or ex-smokers, of at least 18 years ofage with a body mass index greater than or equal to 18.50 and below30.00 kg/m² were included in the study. Subjects were in good health asdetermined by a medical history, complete physical examination(including vital signs), 12-lead Electrocardiogram (ECG) and the usualclinical laboratory tests (general biochemistry, hematology, urinalysis)including negative Human Immunodeficiency Virus (HIV), Hepatitis B andHepatitis C tests as well as negative urine drug screening of alcohol,cotinine and drugs of abuse and negative beta Human ChorionicGonadotropin (HCG) qualitative serum pregnancy test (for femalesubjects).

Test Product, Dose and Mode of Administration:

-   Name: Ondansetron-   Dosage form/Route of administration: A bimodal tablet of the present    invention (Electrolyte CDT Core)/Oral (“Test Product”)-   Regimen for Treatment-1: Single 24 mg dose (1×24 mg) once daily for    5 consecutive days

Reference Product, Dose and Mode of Administration:

-   Name: Zofran®-   Dosage form/Route of administration: Tablet/Oral-   Regimen for Treatment-2: Single 8 mg dose (1×8 mg) twice daily at an    8-hour interval on Day 1 and at a 12-hour interval on Day 2-   Regimen for Treatment-3: Single 24 mg dose (3×8 mg)

Treatments:

-   Treatment-1: Test administered once daily for 5 consecutive days-   Treatment-2: Reference administered twice daily, at 8-hour intervals    on Day 1 and at 12-hour intervals on Day 2-   Treatment-3: A single 24 mg dose administered as three Reference    tablets taken together

Treatment Periods:

-   Period 1: 2013/08/08 to 2013/08/12 (Treatment-1)-   Period 1: 2013/08/08 to 2013/08/09 (Treatment-2)-   Period 1: 2013/08/08 (Treatment-3)-   Period 2: 2013/08/17 to 2013/08/21 (Treatment-1)-   Period 2: 2013/08/17 to 2013/08/18 (Treatment-2)-   Period 2: 2013/08/17 (Treatment-3)-   Period 3: 2013/08/26 to 2013/08/30 (Treatment-1)-   Period 3: 2013/08/26 to 2013/08/27 (Treatment-2)-   Period 3: 2013/08/26 (Treatment-3)

Duration of Treatment:

-   Treatment-1: A single 24 mg dose of ondansetron (1×24 mg bimodal    tablet (Electrolyte CDT Core)) (“Test Product”) was orally    administered once daily in the morning following a 10-hour overnight    fast for 5 consecutive days.-   Treatment-2: A single 8 mg dose of Zofran® (1×8 mg tablet) was    orally administered twice daily, for two consecutive days, at 8-hour    intervals on Day 1 and at 12-hour intervals on Day 2 (first dose in    the morning of each day following a 10-hour overnight fast, and a    second dose in the afternoon (Day 1) or evening (Day 2)) (for a    total of 4 drug administrations).-   Treatment-3: A single 24 mg dose of Zofran® (3×8 mg tablets) was    orally administered following a 10-hour overnight fast.

The wash-out period between the first drug administrations of each studyperiod was to be of 9 calendar days.

Blood Sampling Points:

During the study, a total of 98 blood samples were collected as follows:

-   Treatment-1: On Days 1 and 2 of dosing, 13 blood samples were    collected per day. The first blood sample was collected prior to    drug administration (within 5 minutes) while the others were    collected 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16 and 20 hours post drug    administration.    -   On Days 3 and 4 of dosing, 8 blood samples were collected per        day, the first blood sample was collected prior to drug        administration (within 5 minutes) while the others were        collected 2, 4, 6, 8, 10, 14 and 18 hours post drug        administration.    -   On Day 5 of dosing, 10 blood samples were collected, the first        blood sample was collected prior to drug administration (within        5 minutes) while the others were collected 2, 4, 6, 8, 10, 14,        18, 24 and 48 hours post drug administration.    -   For a total of 52 samples per subject with this treatment.-   Treatment-2: On Day 1 of dosing, 15 blood samples were collected.    The first blood sample was collected prior to the morning drug    administration (within 5 minutes) while the others were collected 1,    2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 14, 16, and 20 hours following the    morning drug administration. The 8-hour blood sample was collected    within 5 minutes before the afternoon administration.    -   On Day 2 of dosing, 17 blood samples were collected. The first        blood sample was collected prior to the morning drug        administration (within 5 minutes) while the others were        collected 1, 2, 3, 4, 5, 6, 8, 12, 13, 14, 15, 16, 18, 20, 24        and 48 hours following the morning drug administration. The        12-hour blood sample was collected within 5 minutes before the        evening administration.    -   For a total of 32 samples per subject with this treatment.-   Treatment-3: On Day 1 of dosing, 14 blood samples were collected.    The first blood sample was collected prior to the drug    administration (within 5 minutes) while the others were collected 1,    2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 and 48 hours following drug    administration.

Criteria for Evaluation Analytical Method:

-   Analyte: Ondansetron in human plasma-   Method: HPLC with MS/MS detection-   Assay range: 0.500 ng/mL to 300.000 ng/mL

Safety:

Safety was evaluated through assessment of adverse events, standardlaboratory evaluations, vital signs, ECG and physical examination.

Mathematical Model and Statistical Methods of Pharmacokinetic Parameters

Main absorption and disposition parameters using a non-compartmentalapproach with a log-linear terminal phase assumption. Trapezoidal ruleto estimate area under the curve, terminal phase estimation based onmaximizing the coefficient of determination. The pharmacokineticparameters of interest for this study were to be C_(max) for each day ofdosing, AUC₀₋₂₄ for each day of dosing, C_(min) for each day of dosingand C₂₄ for each dosing day. Other parameters including T_(max) for eachdosing day, AUC_(T), AUC_(∞), AUC_(T/∞), K_(el) and T_(1/2el) were to becalculated.

Statistical analysis of all pharmacokinetic parameters based on aparametric random ANOVA model. Two-sided 90% confidence interval of theratio of geometric LSmeans obtained from the ln-transformedpharmacokinetic parameters.

During treatment with the Test product, C_(max) and AUC₀₋₂₄ on Days 2through 5 were to be compared with C_(max) and AUC₀₋₂₄ on Day 1 toassess accumulation with repeated dosing.

Accumulation of the Test formulation was to be evaluated usingln-transformed C_(max) and AUC₀₋₂₄. An Analysis of Variance (ANOVA)model was to be fitted with the day as a fixed effect and the subject asa random effect.

ANOVA Model for Treatments Comparisons:

-   -   fixed factors: sequence, period, treatment    -   random factor: subject (nested within sequence)

ANOVA for Accumulation:

-   -   fixed factors: day    -   random factor: subject

Standards for Comparative Bioavailability:

Concentrations of ondansetron over time after dosing with the Testformulation were to be compared with those after dosing with thereference regimens. A single 24 mg dose of immediate release ondansetronwas considered effective for prevention of nausea and vomiting fromhighly emetogenic cancer chemotherapy, and twice daily 8 mg dosing wasconsidered effective for moderately emetogenic chemotherapy. Therefore,if the concentration of ondansetron after dosing with Test Product wasfound to be similar to or higher than that after dosing with one or bothof the reference regimens at most time points over the first 24-hourperiod studied, one can conclude that the Test product was to be atleast as effective treatment with the existing regimens for moderatelyemetogenic cancer chemotherapy.

Safety:

Descriptive statistics.

Summary of Results Safety Results:

Nine (9) of the 18 subjects (50.0%) included in this study experienced atotal of 28 adverse events. All of the 28 adverse events reported duringthe study were mild in severity. The below table presents the number ofadverse events by treatment classified by severity and causality:

TABLE 20 Number of Patients with Adverse Events Severity Causality Rea-No Rea- sonable sonable Treatments Mild Moderate Severe PossibilityPossibility Test Product 6 0 0 4 4 Zofran 8 mg bid 5 0 0 3 3 Zofran 24mg × 1 6 0 0 3 3 Total number of 9 0 0 7 6 patients with adverse events

Six (6) subjects (33.3%) reported 12 adverse events (2 different SystemOrgan Classes and 7 different Preferred Terms) after the administrationof Treatment-1, 5 subjects (27.8%) reported 7 adverse events (3different System Organ Classes and 5 different Preferred Terms) afterthe administration of Treatment-2 and 6 subjects (33.3%) reported 9adverse events (4 different System Organ Classes and 7 differentPreferred Terms) after the administration of Treatment-3. The number ofsubjects who experienced at least one adverse event during the study wassimilar for all 3 treatments.

Adverse events experienced by two or more subjects with any treatmentcondition were (Treatment-1, Treatment-2, Treatment-3) abnormal faeces(2, 0, 0), constipation (2, 0, 1), vessel puncture site haematoma (2, 3,2), vessel puncture site pain (0, 1, 1), headache (0, 1, 1) andsomnolence (0, 1, 1). Furthermore, related adverse events experienced bytwo or more subjects with any treatment condition were (Treatment-1,Treatment-2, Treatment-3) constipation (2, 0, 1), headache (0, 1, 1) andsomnolence (0, 1, 1).

No serious adverse events or deaths were reported during this study.Moreover, no clinically significant laboratory evaluations, vital signs,ECGs or physical examinations were observed during this study.

No adverse events required the use of medications following the firstdosing.

No subject was withdrawn from the study for safety reasons.

Pharmacokinetic Results: Treatment Comparisons:

The main pharmacokinetic parameters (C_(min), C_(max), C₂₄ and AUC₀₋₂₄)of each treatment were measured for each dosing day. Comparisons betweenthe first 2 days of administration of Test Product with the 2 days ofadministration of Zofran 8 mg bid were performed as well as a comparisonbetween the first day of administration of Test Product with theadministration of Zofran 24 mg. A summary of the results of thesecomparisons is presented in FIGS. 7-13 and Tables 21-24.

TABLE 21 Pharmacokinetic Parameters After Administration of Test ProductTest Product DAY 1 DAY 2 PARAMETER MEAN C.V. (%) MEAN C.V. (%) C_(max)(ng/mL) 54.0 35.3 63.7 42.4 ln (C_(max)) 3.94 8.4 4.08 9.6 C_(min)(ng/mL) 10.2 66.5 13.6 60.1 ln (C_(min)) 2.14 28.1 2.45 23.9 C₂₄ (ng/mL)11.5 64.0 13.7 59.0 ln (C₂₄) 2.27 26.4 2.46 23.2 AUC₀₋₂₄ (ng*h/mL) 637.638.6 796.8 46.6 ln (AUC₀₋₂₄) 6.389 5.9 6.589 6.5

TABLE 22 Pharmacokinetic Parameters After Administration of Zofran 8 mgbid Zofran 8 mg bid DAY 1 DAY 2 PARAMETER MEAN C.V. (%) MEAN C.V. (%)C_(max) (ng/mL) 46.0 38.7 46.6 45.6 ln (C_(max)) 3.77 9.0 3.76 11.1C_(min) (ng/mL) 8.72 73.2 11.6 69.3 ln (C_(min)) 1.95 34.5 2.26 27.1 C₂₄(ng/mL) 8.72 73.2 13.6 68.5 ln (C₂₄) 1.95 34.5 2.42 26.0 AUC₀₋₂₄(ng*h/mL) 539.5 43.2 606.9 49.4 ln (AUC₀₋₂₄) 6.211 6.5 6.306 7.2

TABLE 23 Pharmacokinetic Parameters After Administration of Zofran 24 mg× 1 Zofran 24 mg × 1 DAY 1 PARAMETER MEAN C.V. (%) C_(max) (ng/mL) 14031.5 ln (C_(max)) 4.90 6.0 C_(min) (ng/mL) 8.07 68.9 ln (C_(min)) 1.9033.0 C₂₄ (ng/mL) 8.07 68.9 ln (C₂₄) 1.90 33.0 AUC₀₋₂₄ (ng*h/mL) 105834.4 ln (AUC₀₋₂₄) 6.913 4.6

TABLE 24 Treatment Comparisons (Continued) INTRA- 90% CONFIDENCE SUBJECTGEOMETRIC LSMEANS* RATIO LIMITS (%) Comparison DAY C.V. (%) Test ProductTREATMENT** (%) LOWER UPPER C_(max) Test Product vs Zofran 8 mg bid 113.6 51.2 43.3 118 109 128 Test Product vs Zofran 24 mg × 1 1 13.6 51.2135 38.1 35.3 41.1 Test Product vs Zofran 8 mg bid 2 11.1 59.0 42.7 138130 147 C_(min) Test Product vs Zofran 8 mg bid 1 28.1 8.50 7.04 121 103141 Test Product vs Zofran 24 mg × 1 1 28.1 8.50 6.69 127 109 148 TestProduct vs Zofran 8 mg bid 2 22.7 11.5 9.61 120 105 137 C₂₄ Test Productvs Zofran 8 mg bid 1 26.6 9.69 7.04 138 119 160 Test Product vs Zofran24 mg × 1 1 26.6 9.69 6.69 145 125 168 Test Product vs Zofran 8 mg bid 223.8 11.7 11.3 104 90.9 120 AUC₀₋₂₄ Test Product vs Zofran 8 mg bid 112.2 595.4 498.4 119.5 111.6 127.9 Test Product vs Zofran 24 mg × 1 112.2 595.4 1005 59.22 55.30 63.42 Test Product vs Zofran 8 mg bid 2 12.4726.9 547.9 132.7 123.5 142.6 *Units are ng/mL for C_(max), C_(min) andC₂₄ and ng*h/mL for AUC₀₋₂₄ **Refers to Zofran 8 mg bid or Zofran 24 mg× 1 according to the comparison

Concentration Comparisons:

Concentrations of ondansetron at selected time points after dosing withTest Product were compared with those after dosing with Zofran 8 mg bidand Zofran 24 mg×1. Measured concentrations achieved with Test Productat 10, 12 14 and 16 hours post-dose for Day 1 and at 20 hours post-dosefor Day 2 were compared to the respective measured concentrations ofondansetron achieved with the administration of the other treatments. Asummary of the results of these comparisons is presented in thefollowing tables.

TABLE 25 Concentration After Administration of Test Product Test ProductPARAMETER DAY MEAN C.V. (%) C₁₀ (ng/mL) 1 30.2 40.3 ln (C₁₀) 1 3.33 13.0C₁₂ (ng/mL) 1 25.0 42.8 ln (C₁₂) 1 3.14 13.4 C₁₄ (ng/mL) 1 20.7 48.1 ln(C₁₄) 1 2.93 15.4 C₁₆ (ng/mL) 1 17.7 51.9 ln (C₁₆) 1 2.76 17.8 C₂₀(ng/mL) 1 12.8 57.9 ln (C₂₀) 1 2.41 22.3 N/AP: Not applicable

TABLE 26 Concentration After Administration of Zofran 8 mg bid Zofran 8mg bid PARAMETER DAY MEAN C.V. (%) C₁₀ (ng/mL) 1 44.7 37.4 ln (C₁₀) 13.74 8.9 C₁₂ (ng/mL) 1 32.9 44.1 ln (C₁₂) 1 3.41 12.2 C₁₄ (ng/mL) 1 24.148.2 ln (C₁₄) 1 3.08 15.5 C₁₆ (ng/mL) 1 19.2 56.7 ln (C₁₆) 1 2.82 18.8C₂₀ (ng/mL) 1 12.2 63.1 ln (C₂₀) 1 2.33 26.3

TABLE 27 Concentration After Administration of Zofran 24 mg × 1 Zofran24 mg × 1 PARAMETER DAY MEAN C.V. (%) C₁₀ (ng/mL) 1 37.9 40.1 ln (C₁₀) 13.56 11.4 C₁₂ (ng/mL) 1 27.4 44.2 ln (C₁₂) 1 3.22 13.4 C₁₄ (ng/mL) 1N/AP N/AP ln (C₁₄) 1 N/AP N/AP C₁₆ (ng/mL) 1 16.0 54.8 ln (C₁₆) 1 2.6419.6 C₂₀ (ng/mL) 1 10.8 60.6 ln (C₂₀) 1 2.23 25.5

TABLE 28 Concentration Comparisons After Administration 90% INTRA-GEOMETRIC LSMEANS CONFIDENCE SUBJECT (ng/mL) RATIO LIMITS (%) ComparisonParameter Day C.V. (%) Test Product TREATMENT* (%) LOWER UPPER TestProduct vs C₁₀ 1 18.9 27.8 42.3 65.8 59.2 73.1 Zofran 8 mg bid TestProduct vs C₁₀ 1 18.9 27.8 35.1 79.2 71.3 88.0 Zofran 24 mg × 1 TestProduct vs C₁₂ 1 16.9 23.0 30.3 76.0 69.1 83.5 Zofran 8 mg bid TestProduct vs C₁₂ 1 16.9 23.0 25.1 91.5 83.2 101 Zofran 24 mg × 1 TestProduct vs C₁₄ 1 21.7 18.7 21.7 86.4 76.2 98.0 Zofran 8 mg bid TestProduct vs C₁₆ 1 18.9 15.7 16.8 93.7 84.2 104 Zofran 8 mg bid TestProduct vs C₁₆ 1 18.9 15.7 14.1 112 101 124 Zofran 24 mg × 1 TestProduct vs C₂₀ 1 22.6 11.1 10.3 108 95.5 123 Zofran 8 mg bid TestProduct vs C₂₀ 1 22.6 11.1 9.28 120 106 136 Zofran 24 mg × 1 *Refers toZofran 8 mg bid or Zofran 24 mg × 1 according to the comparison

Accumulation Evaluation:

In order to evaluate the accumulation of ondansetron after multipleadministrations of Test Product, C_(max) and AUC₀₋₂₄ were measured for 5consecutive days of dosing and compared to the single doseadministration of Test Product at Day 1. A summary of the results ispresented in the following tables.

TABLE 29 Accumulation Evaluation of Test Product - C_(max) INTRA-GEOMETRIC LSMEANS 90% CONFIDENCE SUBJECT (ng/mL) RATIO LIMITS (%)Comparison C.V. (%) DAY* DAY 1 (%) LOWER UPPER Day 2 vs Day 1 8.8 59.051.2 115 110 121 Day 3 vs Day 1 8.8 60.6 51.2 118 113 124 Day 4 vs Day 18.8 62.7 51.2 122 117 129 Day 5 vs Day 1 8.8 64.1 51.2 125 119 131*Refers to Day 2, 3, 4 or 5 according to the comparison

TABLE 30 Accumulation Evaluation of Test Product - AUC₀₋₂₄ INTRA-GEOMETRIC LSMEANS 90% CONFIDENCE SUBJECT (ng*h/mL) RATIO LIMITS (%)Comparison C.V. (%) DAY* DAY 1 (%) LOWER UPPER Day 2 vs Day 1 9.1 726.9595.4 122.1 116.1 128.4 Day 3 vs Day 1 9.1 743.8 595.4 125.0 118.8 131.4Day 4 vs Day 1 9.1 781.3 595.4 131.2 124.7 138.0 Day 5 vs Day 1 9.1784.0 595.4 131.7 125.2 138.5 *Refers to Day 2, 3, 4 or 5 according tothe comparison

Pharmacokinetic Discussion: Treatment Comparisons:

Test Product vs Zofran 8 mg bid:

The results presented herein show that the C_(min) and C_(max) over 24hours as well as AUC₀₋₂₄ were higher during the first two days ofadministration of Test Product as compared to both days ofadministration of Zofran 8 mg bid.

The C₂₄ was found to be higher with the administration of Test Productfor the first day of treatment and was found to be comparable betweenTest Product and Zofran 8 mg bid for the second day of treatment.

Test Product Vs Zofran 24 mg×1:

The C_(min) and C₂₄ were also higher for the first day of administrationof Test Product as compared to the administration of Zofran 24 mg×1.

However, the C_(max) and AUC₀₋₂₄ achieved with the administration ofTest Product were about 60% (ratio of 38%) and 40% (ratio of 59%) lowerthan the C_(max) and AUC₀₋₂₄ achieved with the administration of Zofran24 mg×1.

Concentration Comparisons:

Test Product Vs Zofran 8 mg Bid:

Measured concentrations from 3 through 8 hours after initial dosing werehigher after administration of Test Product. At 10 and 12 hours,concentrations were found to be lower with the administration of TestProduct for the first day of treatment; subsequent concentrations weresimilar between the two groups on the first day.

Due to the later administration of the second dose on day 2, the shapeof the concentration curve for Zofran 8 mg bid was somewhat differentthan on the first day, but the overall results were similar.

Test Product Vs Zofran 24 mg×1:

Measured concentrations through 10 hours were found to be lowerfollowing the administration of Test Product. The measured concentrationat 12 and 16 hours were found to be comparable between the twotreatments and higher for Test Product at 20 and 24 hours.

Accumulation Evaluation

The accumulation evaluation performed on C_(max) demonstrated a first15% increase between Day 1 and Day 2 and also demonstrated a uniformincrease of the ratio estimate based on back-transformation of LS Means'difference throughout Day 3 to Day 5 (118-125% of C_(max) observed onDay 1) indicating the accumulation of ondansetron following multipleadministrations of Test Product. A similar increase was observed forAUC₀₋₂₄ for Day 3 and 4 (125-131% of AUC₀₋₂₄ observed on Day 1)following a 22% increase between Day 1 and Day 2.

The ratio estimate based on back-transformation of LS Means' differencefor the AUC₀₋₂₄ was similar for Day 4 (131%) and Day 5 (132%) indicatingthat steady state had been reached between day 4 and 5 of repeated dailyTest Product administration.

Conclusions: Comparative Bioavailability:

The results presented herein demonstrate that bioavailability of TestProduct is noninferior to that of Zofran 8 mg bid, the approved regimenfor prevention of nausea and vomiting due to moderately emetogenicchemotherapy.

Key points in this comparison:

-   -   Geometric mean AUC₀₋₂₄ of Test Product was 19% higher than that        of Zofran 8 mg bid (90% CI 12-28%) on day 1 of dosing, 33%        higher (90% CI 24-43%) on day 2.    -   Geometric mean C_(max) of Test Product was 18% higher than that        of Zofran 8 mg bid (90% CI 9-28%) on day 1 of dosing, 38% higher        on day 2 (90% CI 30-47%).    -   Both C₂₄ and C_(min) of Test Product were higher than those of        both Zofran 8 mg bid and

Zofran 24 mg×1

-   -   Ondansetron levels were similar to or higher after Test Product        than after Zofran 8 mg at all time points except 10 and 12 hours        after initial dosing on day 1 and 14-20 hours on day 2.        -   At 10 and 12 hours after dosing on day 1, the levels after            Test Product were 107% and 72% higher than the trough            ondansetron level 8 hours after the initial dose of Zofran 8            mg.        -   At 14-20 hours after initial dosing on day 2, levels after            Test Product were 47-159% higher than the trough ondansetron            level 12 hours after the initial dose of Zofran 8 mg.    -   In addition, from 12 hours on, levels of ondansetron after Test        Product were similar to or higher than levels after Zofran 24        mg×1, which is the approved regimen for highly emetogenic        chemotherapy.

The plasma level of ondansetron after Test Product is similar to orhigher than the plasma level after Zofran 8 mg given twice daily at mosttime points tested, and the concentrations at other time points areconsiderably higher than trough levels at 8 or 12 hours (days 1 and 2respectively) after the initial dose for the reference regimen of Zofran8 mg twice daily. Therefore, it is reasonable to conclude that theefficacy of Test Product is at least as good as that of the Zofran 8 mgtwice daily.

Accumulation Assessment:

The once daily administration of Test Product for 5 consecutive daysunder fasting conditions confirmed an accumulation of ondansetron inhuman plasma. Maximum plasma concentrations increased from 15% to 25%from Day 2 to Day 5. Following the first 15% increase, an increase of≈3% of the maximum concentration was observed for each subsequent dosingday. AUC₀₋₂₄ increased from 22 to 31% from Day 2 to Day 4 andsubsequently stabilized to 32% for Day 5 indicating arrival at a steadystate situation.

Safety and Tolerability of Test Product:

The results presented herein show that the once daily administration ofTest Product for 5 consecutive days was safe and well tolerated by thesubjects included in this study. Furthermore, the number of subjects whoexperienced at least one adverse event was comparable between alltreatment groups and all of the 28 adverse events reported during thestudy were mild in severity, demonstrating that the safety andtolerability of the extended-release formulation, Test Product, wassimilar to the safety profile of the other treatments.

Despite some drug accumulation with repeated dosing, there was noindication that this resulted in any safety issues. In particular, theincidence of mild QTc prolongation was higher after a single 24 mg doseof immediate release Zofran than it was after 5 daily doses of TestProduct.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising a non-ionic polymer matrix,a first amount of a first antiemetic drug or a pharmaceuticallyacceptable salt thereof dispersed within the matrix, and a saltdispersed within the matrix; a first seal coat surrounding the core,wherein the first seal coat is comprised of a non-ionic polymer matrix;and an immediate release drug layer surrounding the first seal coat,wherein the immediate release drug layer comprises a non-ionic polymerand a second amount of a second antiemetic drug or a pharmaceuticallyacceptable salt thereof dispersed therein, wherein the drug layer issufficiently designed to release the second amount of the antiemeticdrug over a period of at least 1 hour, wherein the solid oral dosageform is sufficiently designed to release the first amount of the firstantiemetic drug and the second amount of the second antiemetic drug overa minimum period of 16 hours. In an embodiment, the solid oral dosageform further includes an enteric coating surrounding the first sealcoat. In an embodiment, the solid oral dosage form further includes asecond seal coat surrounding the immediate release drug layer, whereinthe second seal coat is comprised of a non-ionic polymer. In anembodiment, the first seal coat further comprises a coating additivesuch as plasACRYL™ In an embodiment, the salt in the core is dispersedin the matrix at a concentration in the range of 50% to 100% by weightof the matrix. In an embodiment, upon exposure of the solid dosage formto an aqueous medium, the salt causes a hardened boundary around theperiphery of the matrix, the boundary sequentially progressing inwardlytoward the center thereof as the aqueous medium permeates the matrix,the hardened boundary limiting the rate at which the antiemetic drug inthe matrix is released from the tablet. In an embodiment, the solid oraldosage form is sufficiently designed to release the first amount of theantiemetic drug and the second amount of the antiemetic drug over aminimum period of 20 hours. In an embodiment, the solid oral dosage formis sufficiently designed to release the first amount of the antiemeticdrug and the second amount of the antiemetic drug over a minimum periodof 24 hours. In an embodiment, the first antiemetic drug and the secondantiemetic drug are the same drug. In an embodiment, the firstantiemetic drug and the second antiemetic drug are each ondansetron oran equivalent amount of an ondansetron salt thereof.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising hypromellose, 18 mg ofondansetron or an equivalent amount of an ondansetron salt thereof, andsodium citrate anhydrous; a first seal coat surrounding the core andcomprising hypromellose; and an immediate release drug layer surroundingthe first seal coat and comprising hypromellose and 6 mg of ondansetronor an equivalent amount of an ondansetron salt thereof, the immediaterelease drug layer sufficient to release the ondansetron over a periodof at least 1 hour, wherein the total amount of ondansetron in thedosage form is released over 24 hours. In an embodiment, the solid oraldosage form further includes an enteric coating surrounding the firstseal coat. In an embodiment, the solid oral dosage form further includesa second seal coat surrounding the immediate release drug layer, whereinthe second seal coat is comprised of a non-ionic polymer. In anembodiment, the first seal coat further comprises a coating additivesuch as plasACRYL™. In an embodiment, the sodium citrate anhydrous inthe core is dispersed in the hypromellose at a concentration in therange of 50% to 100% by weight of the hypromellose. In an embodiment,upon exposure of the solid oral dosage form to an aqueous medium, thesodium citrate anhydrous causes a hardened boundary around the peripheryof the hypromellose, the boundary sequentially progressing inwardlytoward the center thereof as the aqueous medium permeates thehypromellose, the hardened boundary limiting the rate at which theondansetron in the hypromellose is released from the tablet. In anembodiment, when the solid oral dosage form is administered to a patientin a fasting state, achieves a C_(max) of at least 50 ng/ml. In anembodiment, when the solid oral dosage form is administered to a patientin a fasting state, achieves AUC of at least 600 nghr/ml.

According to aspects illustrated herein, there is disclosed a solid oraldosage form that includes a core comprising a non-ionic polymer matrix,a first amount of ondansetron or an equivalent amount of an ondansetronsalt thereof dispersed within the matrix, and a salt dispersed withinthe matrix; a first seal coat surrounding the core, wherein the firstseal coat is comprised of a non-ionic polymer matrix; and an immediaterelease drug layer surrounding the first seal coat, wherein theimmediate release drug layer comprises a non-ionic polymer and a secondamount of ondansetron or an equivalent amount of an ondansetron saltthereof dispersed therein, wherein the solid oral dosage form results inan in vitro ondansetron dissolution profile when measured in a type 2paddle dissolution apparatus at 37° C. in aqueous solution containingdistilled water at 50 rpm that exhibits: a) from about 20% to 50% of thetotal ondansetron is released after two and a half hours of measurementin the apparatus; b) from about 50% to 70% of the total ondansetron isreleased after five hours of measurement in the apparatus; and c) noless than about 90% of the total ondansetron is released after fifteenhours of measurement in the apparatus. In an embodiment, when the solidoral dosage form is administered to a patient in a fasting state at adose of 24 mg ondansetron, achieves a C_(max) of at least 50 ng/ml. Inan embodiment, when the solid oral dosage form is administered to apatient in a fasting state at to dose of 24 mg ondansetron, achieves AUCof at least 600 nghr/ml.

According to aspects illustrated herein, there is disclosed a packagedpharmaceutical preparation that includes a plurality of any of the solidoral dosage forms of the present invention in a sealed container andinstructions for administering the dosage forms orally to effectprevention of nausea and vomiting

According to aspects illustrated herein, there is disclosed apharmaceutical preparation that includes a plurality of any of the solidoral dosage forms of the present invention each in a discrete sealedhousing, and instructions for administering the dosage forms orally toeffect prevention of nausea and vomiting.

According to aspects illustrated herein, there is disclosed a unitdosage form for oral administration to a patient, wherein the unitdosage form is sufficiently designed for preventing nausea and vomitingin the patient, and wherein the unit dosage form includes a combinationof an immediate release ondansetron component containing a unit dosageof ondansetron or a pharmaceutically acceptable salt thereof in therange of 4 mg to 8 mg; and a controlled release ondansetron componentcontaining a unit dosage of ondansetron or a pharmaceutically acceptablesalt thereof in the range of 16 mg to 28 mg, the controlled releaseondansetron component comprising a non-ionic polymer matrix, theondansetron within the matrix, and a salt dispersed within the matrix,and wherein the unit dosage form exhibits a maximum plasma concentration(Cmax) at about 2 to about 5 hours (Tmax) after administration andexhibits a comparable Cmax to a non-controlled release ondansetronformulation administered three times per day without decreasing totaldrug exposure defined by the area under the concentration-time curve(AUC), thereby enabling reduction of concentration-dependent sideeffects without a decrease in efficacy.

A packaged pharmaceutical preparation that includes a plurality of theunit dosage forms of the present invention can be contained within asealed container and include instructions for administering the dosageforms orally to effect prevention of nausea and vomiting.

A packaged pharmaceutical preparation that includes a plurality of theunit dosage forms of the present invention can be contained within adiscrete sealed housing and include instructions for administering thedosage forms orally to effect prevention of nausea and vomiting.

A method for preventing nausea and vomiting includes the step ofadministering a therapeutically-effective amount of a solid oral dosageform or a unit dosage form of the present invention to a patient.

According to aspects illustrated herein, there is disclosed a once-a-daycomposition that includes: (a) a core comprising a non-ionic polymermatrix, a first amount of ondansetron or an equivalent amount of anondansetron salt dispersed within the matrix, and a salt dispersedwithin the matrix; (b) a first seal coat surrounding the core, whereinthe first seal coat is comprised of a non-ionic polymer matrix; and (c)an immediate release drug layer surrounding the enteric coating, whereinthe immediate release drug layer comprises a non-ionic polymer and asecond amount of ondansetron or an equivalent amount of an ondansetronsalt dispersed therein, wherein the immediate release drug layer issufficiently designed to release the second amount of ondansetron over aperiod of at least 1 hour, wherein the immediate release drug layerreleases the second amount of ondansetron in the upper gastrointestinaltract of a human patient, wherein the core releases the first amount ofondansetron in the lower gastrointestinal tract of a human patient,wherein the composition is a tablet or capsule that contains 24 to 40 mgof ondansetron or an equivalent amount of an ondansetron salt, andprovides an in vivo plasma profile selected from: (a) a mean C_(max) ofat least 50.0 ng/ml; (b) a mean AUC₀₋₂₄ of greater than 550.0 nghr/ml;and (c) a mean T_(max) of between approximately 2.0 hours and 5.0 hours.In an embodiment, the once-a-day composition, when administeredonce-a-day to a human in a fasted state, is bioequivalent toadministration to a human in a fasted state, three-times-a-day, a unitdosage form comprising 8 mg ondansetron. In an embodiment, thebioequivalency is established by a 90% Confidence Interval of between0.80 and 1.25 for both C_(max) and AUC, when administered to a human. Inan embodiment, solubility and dissolution characteristics arepH-independent. In an embodiment, the core has a pH-independentdissolution release profile over a pH range of 1.2-6.8. In anembodiment, each of the core and the immediate release drug layer has apH-independent dissolution release profile over a pH range of 1.2-6.8.In an embodiment, each of the core and the immediate release drug layerare surrounded by a seal coat comprised of a non-ionic polymer whichincreases hydrophilicity of the composition and as a result thedissolution profile of the composition is pH-independent.

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entirety. It will beappreciated that several of the above-disclosed and other features andfunctions, or alternatives thereof, may be desirably combined into manyother different systems or application. Various presently unforeseen orunanticipated alternatives, modifications, variations, or improvementstherein may be subsequently made by those skilled in the art.

What is claimed is:
 1. A bimodal release ondansetron tablet comprising:an internal portion comprising a hydrophilic swellable matrix, in whichis disposed a first amount of ondansetron or an equivalent amount of anondansetron salt thereof and one or more electrolytes selected from oneor two members of the group consisting of sodium chloride, sodiumbicarbonate, potassium bicarbonate, sodium citrate, sodium bisulfate,sodium sulfite, magnesium sulfate, calcium chloride, potassium chloride,and sodium carbonate; a first seal coat surrounding the internalportion, wherein the first seal coat comprises hypromellose and whereinthe first seal coat does not substantially affect the release of theondansetron from the tablet; an immediate release drug layer overcoatsurrounding the first seal coat and comprising a second amount ofondansetron or an equivalent amount of an ondansetron salt thereof; anda second seal coat surrounding the immediate release drug layer, whereinthe second seal coat comprises hypromellose and wherein the second sealcoat does not substantially affect the release of the ondansetron fromthe tablet.
 2. The bimodal release ondansetron tablet of claim 1,further comprising an enteric coating surrounding the first seal coat.3. The bimodal release ondansetron tablet of claim 1, wherein the firstand second seal coat further comprises a coating additive.
 4. Thebimodal release ondansetron tablet of claim 3, wherein the coatingadditive is an aqueous emulsion of glyceryl monostearate and triethylcitrate.
 5. The bimodal release ondansetron tablet of claim 1, whereinone of the one or more electrolytes is sodium citrate.
 6. The bimodalrelease ondansetron tablet of claim 5, wherein the sodium citrate issodium dihydrogen citrate anhydrous present at a concentration in therange of 50% to 100% by weight of the hydrophilic swellable matrix. 7.The bimodal release ondansetron tablet of claim 1, wherein up to 75% ofthe total dosage form weight is included in the internal portion.
 8. Thebimodal release ondansetron tablet of claim 1, wherein the drug layerovercoat yields a burst of 25% ondansetron.
 9. The bimodal releaseondansetron tablet of claim 1, wherein the second amount of ondansetronis ⅓ the first amount of ondansetron.
 10. The bimodal releaseondansetron tablet of claim 1, wherein the internal portion comprisesthe equivalent of 18 mg of ondansetron and the immediate release layercomprises the equivalent of 6 mg of ondansetron.
 11. A method oftreating nausea in a patient comprising administering the bimodalrelease ondansetron tablet of claim
 1. 12. The method of claim 11,wherein the bimodal release ondansetron tablet is administered oncedaily.
 13. A method of treating vomiting in a patient comprisingadministering the bimodal release ondansetron tablet of claim
 1. 14. Themethod of claim 13, wherein the bimodal release ondansetron tablet isadministered once daily.
 15. A packaged pharmaceutical preparationcomprising a plurality of the bimodal release ondansetron tablets ofclaim 1 in a sealed container and instructions for administering thetablets orally to a patient to treat nausea.
 16. A packagedpharmaceutical preparation comprising a plurality of the bimodal releaseondansetron tablets of claim 1 in a sealed container and instructionsfor administering the tablets orally to a patient to treat vomiting.